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  • 51.
    Kindberg, Elin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Ax, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Fiore, Lucia
    Ist Super Sanita.
    Svensson , Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Ala67Thr Mutation in the Poliovirus Receptor CD155 is a Potential Risk Factor for Vaccine and Wild-Type Paralytic Poliomyelitis2009In: JOURNAL OF MEDICAL VIROLOGY, ISSN 0146-6615 , Vol. 81, no 5, p. 933-936Article in journal (Refereed)
    Abstract [en]

    Poliovirus infections can be asymptomatic or cause severe paralysis. Why some individuals develop paralytic poliomyelitis is unknown, but a role for host genetic factors has been suggested. To investigate if a polymorphism, Ala67Thr, in the poliovirus receptor, which has been found to facilitate increased resistance against poliovirus-induced cell lysis and apoptosis, is associated with increased risk of paralytic poliomyelitis, poliovirus receptor genotyping was undertaken among Italian subjects with vaccine-associated (n = 9), or with wild-type paralytic poliomyelitis (n = 6), and control subjects (n = 71), using RFLP-PCR and pyrosequencing. Heterozygous poliovirus receptor Ala67Thr genotype was found in 13.3% of the patients with paresis and in 8.5% of the controls (Odds Ratio = 1.667). The frequency of Ala67Thr among the controls is in agreement with earlier published data. It is concluded that the Ala67Thr mutation in the poliovirus receptor is a possible risk factor for the development of vaccine-associated or paralytic poliomyelitis associated with wild-type virus.

  • 52.
    Kindberg, Elin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Mickiene, Aukse
    Department of Medicine Karolinska University Hospital Huddinge.
    Ax, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Åkerlind, Britt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Microbiology.
    Vene, Sirkka
    5Swedish Institute for Infectious Disease Control Karolinska Institutet, Stockholm.
    Lindquist, Lars
    Department of Medicine Karolinska University Hospital Huddinge.
    Lundkvist, Åke
    Swedish Institute for Infectious Disease Control Karolinska Institutet, Stockholm.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    A deletion in the chemokine receptor 5 (CCR5) gene is associated with tickborne encephalitis2008In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 197, no 2, p. 266-269Article in journal (Refereed)
    Abstract [en]

    Tickborne encephalitis (TBE) virus infections can be asymptomatic or cause moderate to severe injuries of the central nervous system. Why some individuals develop severe disease is unknown, but a role for host genetic factors has been suggested. To investigate whether chemokine receptor CCR5 is associated with TBE, CCR5Δ32 genotyping was performed among Lithuanian patients with TBE (n = 129) or with aseptic meningoencephalitis (n = 76) as well as among control subjects (n = 134). We found individuals homozygous for CCR5Δ32 (P = .026) only among patients with TBE and a higher allele prevalence among patients with TBE compared with the other groups studied. CCR5Δ32 allele prevalence also increased with the clinical severity of disease. © 2007 by the Infectious Diseases Society of America. All rights reserved.

  • 53.
    Kindberg, Elin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Genetic basis of host resistance to norovirus infection2009In: FUTURE VIROLOGY, ISSN 1746-0794, Vol. 4, no 4, p. 369-382Article, review/survey (Refereed)
    Abstract [en]

    Noroviruses have emerged as a major cause of acute gastroenteritis in humans of all ages and are responsible for 200,000 deaths every year, mainly in developing countries. Despite high infectivity and lack of long-term immunity, authentic and volunteer studies have shown existence of inherited protective factors. Recent studies have shown that secretor status controlled by the alpha(1,2)-fucosyltransferase gene located on chromosome 19 determines susceptibility to most, if not all, norovirus infections, with individuals homozygous for the G428A nonsense mutation (nonsecretors) representing 20% of the highly protected European population.

  • 54.
    Kindberg, Elin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Vene, Sirkka
    Swedish Institute Infectious Disease Control.
    Mickiene, Aukse
    Kaunas University of Medicine.
    Lundkvist, Ake
    Swedish Institute Infectious Disease Control.
    Lindquist, Lars
    Karolinska University.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    A Functional Toll-Like Receptor 3 Gene (TLR3) May Be a Risk Factor for Tick-borne Encephalitis Virus (TBEV) Infection2011In: JOURNAL OF INFECTIOUS DISEASES, ISSN 0022-1899, Vol. 203, no 4, p. 523-528Article in journal (Refereed)
    Abstract [en]

    Background. Tick-borne encephalitis virus (TBEV) infections may be asymptomatic or cause severe symptoms in the central nervous system. A mutation in the chemokine receptor 5 gene has been associated with increased risk of TBE but explains only a limited number of cases. Investigations of further risk factors are needed. Method. To investigate the importance of the innate immune response, we analyzed 128 TBE patients, 77 patients with aseptic meningoencephalitis (AME) and 135 healthy controls, for 3mutations: 2 in the Toll-like receptor 3 (TLR3) gene and 1 in the 2-5-oligoadenylate synthetase (OAS1) gene. Results. Although no association was found between the mutation in the OAS1 gene and TBE, the genotype distribution ofrs3775291, a mutation in TLR3, differed significantly between TBE patients and controls; 61%, 32%, and 7% of the TBE patients were carriers of the wild-type, heterozygous, and mutant genotype of rs3775291, respectively. The corresponding percentages among healthy controls (n = 126) were 52%, 29%, and 19% (P = .02), and among AME patients (n = 75) were 47%, 32%, and 21% (P = .009). Additionally, the wild-type rs3775291 allele was more common among TBE patients than among healthy controls (allele frequency, .768 vs .663; P = .01). Conclusion. A functional TLR3 is a risk factor for TBEV infection.

  • 55.
    Kindberg, Elin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Vene, Sirkka
    Swedish Institute for Infectious Disease Control and Karolinska Institutet, Stockholm, Sweden.
    Mickiene, Aukse
    Clinic of Infectious Diseases, Kaunas University of Medicine, Kaunas, Lithuania.
    Lundkvist, Åke
    Swedish Institute for Infectious Disease Control and Karolinska Institutet, Stockholm, Sweden.
    Lindquist, Lars
    Unit for Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    A Missense Mutation in the Toll‐like Receptor 3 Gene (TLR3) is Associated with Decreased Risk of Tick‐borne EncephalitisManuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    Infections with tick‐borne encephalitis virus (TBEV) may be asymptomatic or cause severe symptoms from the central nervous system, such as meningitis or encephalitis. A mutation in the chemokine receptor 5 (CCR5) gene has been associated with increased risk of TBE but can only explain a limited number of cases and investigations of further risk factors are clearly needed. To investigate the importance of the innate immune response, 128 Lithuanian TBE patients with meningitis or encephalitis, 77 patients with aseptic meningoencephalitis (AME) and 135 healthy controls were analyzed for three mutations: two in the toll‐like receptor 3 (TLR3) gene and one in the 2´‐5´ oligoadenylate synthetase 1 (OAS1) gene. While no association was found between the mutation in OAS1 and TBE, the genotype distribution of one of the mutations in TLR3, rs3775291, differed significantly between the TBE patients and the controls. 61%, 32% and 7% of the TBE patients (n=127) were carriers of the wild‐type/wild‐type, heterozygous and mutant/mutant genotype of TLR3 rs3775291 genotype respectively. The corresponding percentages for healthy controls (n=126) were 52%, 29% and 19% (P=0.02) and for AME patients (n=75) 47%, 32% and 21% (P=0.009). The wild‐type rs3775291 allele was more common among TBE patients than healthy controls (allele frequency 0.768 vs. 0.663, P=0.01), suggesting that functional TLR3 is a risk factor for severe TBEV infection.

  • 56.
    Larsson, Marie
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    The dendritic cell: The Immune system's adjuvant-a strategy to develop a HCV vaccine?2006In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 130, no 2, p. 603-606Other (Other academic)
    Abstract [en]

    [No abstract available]

  • 57.
    Larsson, Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Shankar, Esaki M.
    University of Malaya, Malaysia .
    Che, Karlhans F.
    Karolinska Institute, Sweden .
    Saeidi, Alireza
    University of Malaya, Malaysia .
    Ellegård, Rada
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Barathan, Muttiah
    University of Malaya, Malaysia .
    Velu, Vijayakumar
    Emory University, GA USA .
    Kamarulzaman, Adeeba
    University of Malaya, Malaysia .
    Molecular signatures of T-cell inhibition in HIV-1 infection2013In: Retrovirology, ISSN 1742-4690, E-ISSN 1742-4690, Vol. 10, no 1Article, review/survey (Refereed)
    Abstract [en]

    Cellular immune responses play a crucial role in the control of viral replication in HIV-infected individuals. However, the virus succeeds in exploiting the immune system to its advantage and therefore, the host ultimately fails to control the virus leading to development of terminal AIDS. The virus adopts numerous evasion mechanisms to hijack the host immune system. We and others recently described the expression of inhibitory molecules on T cells as a contributing factor for suboptimal T-cell responses in HIV infection both in vitro and in vivo. The expression of these molecules that negatively impacts the normal functions of the host immune armory and the underlying signaling pathways associated with their enhanced expression need to be discussed. Targets to restrain the expression of these molecular markers of immune inhibition is likely to contribute to development of therapeutic interventions that augment the functionality of host immune cells leading to improved immune control of HIV infection. In this review, we focus on the functions of inhibitory molecules that are expressed or secreted following HIV infection such as BTLA, CTLA-4, CD160, IDO, KLRG1, LAG-3, LILRB1, PD-1, TRAIL, TIM-3, and regulatory cytokines, and highlight their significance in immune inhibition. We also highlight the ensemble of transcriptional factors such as BATF, BLIMP-1/PRDM1, FoxP3, DTX1 and molecular pathways that facilitate the recruitment and differentiation of suppressor T cells in response to HIV infection.

  • 58.
    Lubong Sabado, Rachel
    et al.
    NYU.
    OBrien, Meagan
    NYU.
    Subedi, Abhignya
    NYU.
    Qin, Li
    NIAID.
    Hu, Nan
    NIAID.
    Taylor, Elizabeth
    NIAID.
    Dibben, Oliver
    NIAID.
    Stacey, Andrea
    NIAID.
    Fellay, Jacques
    NIAID.
    Shianna, Kevin V
    NIAID.
    Siegal, Frederick
    St Vincent Catholic Medical Centre.
    Shodell, Michael
    St Vincent Catholic Medical Centre.
    Shah, Kokila
    St Vincent Catholic Medical Centre.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Lifson, Jeffrey
    NCI.
    Nadas, Arthur
    NYU.
    Marmor, Michael
    NYU.
    Hutt, Richard
    NYU.
    Margolis, David
    NIAID.
    Garmon, Donald
    NIAID.
    Markowitz, Martin
    NIAID.
    Valentine, Fred
    NYU.
    Borrow, Persephone
    NIAID.
    Bhardwaj, Nina
    NYU.
    Evidence of dysregulation of dendritic cells in primary HIV infection2010In: BLOOD, ISSN 0006-4971, Vol. 116, no 19, p. 3839-3852Article in journal (Refereed)
    Abstract [en]

    Myeloid and plasmacytoid dendritic cells (DCs) are important mediators of both innate and adaptive immunity against pathogens such as HIV. During the course of HIV infection, blood DC numbers fall substantially. In the present study, we sought to determine how early in HIV infection the reduction occurs and whether the remaining DC subsets maintain functional capacity. We find that both myeloid DC and plasmacytoid DC levels decline very early during acute HIV infection. Despite the initial reduction in numbers, those DCs that remain in circulation retain their function and are able to stimulate allogeneic T-cell responses, and up-regulate maturation markers plus produce cytokines/chemokines in response to stimulation with TLR7/8 agonists. Notably, DCs from HIV-infected subjects produced significantly higher levels of cytokines/chemokines in response to stimulation with TLR7/8 agonists than DCs from uninfected controls. Further examination of gene expression profiles indicated in vivo activation, either directly or indirectly, of DCs during HIV infection. Taken together, our data demonstrate that despite the reduction in circulating DC numbers, those that remain in the blood display hyperfunctionality and implicates a possible role for DCs in promoting chronic immune activation.

  • 59.
    Lundgren, Ove
    et al.
    University of Gothenburg.
    Jodal, Mats
    University of Gothenburg.
    Jansson, Madeleine
    University of Gothenburg.
    T Ryberg, Anders
    University of Gothenburg.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Intestinal Epithelial Stem/Progenitor Cells Are Controlled by Mucosal Afferent Nerves2011In: PLOS ONE, ISSN 1932-6203, Vol. 6, no 2, p. 16295-Article in journal (Refereed)
    Abstract [en]

    Background: The maintenance of the intestinal epithelium is of great importance for the survival of the organism. A possible nervous control of epithelial cell renewal was studied in rats and mice. Methods: Mucosal afferent nerves were stimulated by exposing the intestinal mucosa to capsaicin (1.6 mM), which stimulates intestinal external axons. Epithelial cell renewal was investigated in the jejunum by measuring intestinal thymidine kinase (TK) activity, intestinal H-3-thymidine incorporation into DNA, and the number of crypt cells labeled with BrdU. The influence of the external gut innervation was minimized by severing the periarterial nerves. Principal Findings: Luminal capsaicin increased all the studied variables, an effect nervously mediated to judge from inhibitory effects on TK activity or H-3-thymidine incorporation into DNA by exposing the mucosa to lidocaine (a local anesthetic) or by giving four different neurotransmitter receptor antagonists i.v. (muscarinic, nicotinic, neurokinin1 (NK1) or calcitonin gene related peptide (CGRP) receptors). After degeneration of the intestinal external nerves capsaicin did not increase TK activity, suggesting the involvement of an axon reflex. Intra-arterial infusion of Substance P (SP) or CGRP increased intestinal TK activity, a response abolished by muscarinic receptor blockade. Immunohistochemistry suggested presence of M3 and M5 muscarinic receptors on the intestinal stem/progenitor cells. We propose that the stem/progenitor cells are controlled by cholinergic nerves, which, in turn, are influenced by mucosal afferent neuron(s) releasing acetylcholine and/or SP and/or CGRP. In mice lacking the capsaicin receptor, thymidine incorporation into DNA and number of crypt cells labeled with BrdU was lower than in wild type animals suggesting that nerves are important also in the absence of luminal capsaicin, a conclusion also supported by the observation that atropine lowered thymidine incorporation into DNA by 60% in control rat segments. Conclusion: Enteric nerves are of importance in maintaining the intestinal epithelial barrier.

  • 60.
    Mittelholzer, C.
    et al.
    Department of Virology, Swed. Inst. for Infect. Dis. Control, Solna, Sweden, Department of Aquaculture, Institute of Marine Research, Storebø, Norway.
    Englund, L.
    Department of Small Animals, National Veterinary Institute, Uppsala, Sweden.
    Hedlund, K.-O.
    Dept. of Molec. Epidemiol./Biotech., Swed. Inst. for Infect. Dis. Control, Solna, Sweden.
    Dietz, H.-H.
    Dept. of Poultry, Fish/Fur Animals, Danish Veterinary Institute, Arhus, Denmark.
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Detection and Sequence Analysis of Danish and Swedish Strains of Mink Astrovirus2003In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 41, no 11, p. 5192-5194Article in journal (Refereed)
    Abstract [en]

    The sequences of mink astroviruses collected from 11 farms in Denmark and Sweden were analyzed and found to be homologous with one another but different from those of other astroviruses. A species-specific reverse transcriptase-PCR for mink astrovirus was established and shown to be suitable for the analysis of clinical samples.

  • 61.
    Modin Larsson, Malin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Rydell, Gustaf
    Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, Göteborg.
    Grahn, Ammi
    Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, Göteborg.
    Rodríguez-Díaz, Jesús
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Åkerlind, Britt
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Microbiology.
    Hutson, Anne
    Departments of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA .
    Estes, Mary
    Departments of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA.
    Larson, Göran
    Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, Göteborg.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Antibody Prevalence and Titer to Norovirus (Genogroup II) Correlate with Secretor (FUT2) but Not with ABO Phenotype or Lewis (FUT3) Genotype2006In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 194, no 10, p. 1422-1427Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Histo-blood group antigens and secretor status have been associated with susceptibility to Norovirus infections, which suggests that antibody prevalence and titer might correlate with these phenotypes.

    METHODS:

    Plasma samples (n = 105) from Swedish blood donors that had been genotyped for secretor (FUT2) and Lewis (Le; FUT3) genotypes and phenotyped for ABO and Le blood groups were analyzed for immunoglobulin G antibody prevalence and titers to norovirus genogroup (GG) II.4.

    RESULTS:

    The results showed that nonsecretors (se4128se428) and Lea+b- individuals not only had significantly lower antibody titers than did secretors (P < .0001) and Lea-b+ individuals (P < .0002) but were also significantly more often antibody negative (P < .05). Antibody titers in secretors were not significantly different between individuals of different Le (FUT3) genotypes or different ABO phenotypes.

    CONCLUSIONS:

    Nonsecretors and Lea+b- individuals are significantly less prone to be infected with GGII noroviruses. This new information extends previous knowledge and supports the hypothesis that nonsecretors are relatively but not absolutely resistant to norovirus infections.

  • 62.
    Munster, Vincent J.
    et al.
    Erasmus Medical Center, Rotterdam, the Netherlands.
    Wallensten, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Baas, Chantal
    Erasmus Medical Center, Rotterdam, the Netherlands.
    Rimmelzwaan, Guus F.
    Erasmus Medical Center, Rotterdam, the Netherlands.
    Schutten, Martin
    Erasmus Medical Center, Rotterdam, the Netherlands.
    Olsen, Björn
    Umea University, Umea, Sweden.
    Osterhaus, Albert D.M.E
    Erasmus Medical Center, Rotterdam, the Netherlands.
    Fouchier, Ron A.M
    Erasmus Medical Center, Rotterdam, the Netherlands.
    Mallards and highly pathogenic avian influenza ancestral viruses, northern Europe2005In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 11, no 10, p. 1545-1551Article in journal (Refereed)
    Abstract [en]

    Outbreaks of highly pathogenic avian influenza (HPAI), which originate in poultry upon transmission of low pathogenic viruses from wild birds, have occurred relatively frequently in the last decade. During our ongoing surveillance studies in wild birds, we isolated several influenza A viruses of hemagglutinin subtype H5 and H7 that contain various neuraminidase subtypes. For each of the recorded H5 and H7 HPAI outbreaks in Europe since 1997, our collection contained closely related virus isolates recovered from wild birds, as determined by sequencing and phylogenetic analyses of the hemagglutinin gene and antigenic characterization of the hemagglutinin glycoprotein. The minor genetic and antigenic diversity between the viruses recovered from wild birds and those causing HPAI outbreaks indicates that influenza A virus surveillance studies in wild birds can help generate prototypic vaccine candidates and design and evaluate diagnostic tests, before outbreaks occur in animals and humans.

  • 63.
    Munster, V.J.
    et al.
    Department of Virology, Erasmus Medical Center, Rotterdam, Netherlands.
    Baas, C.
    Department of Virology, Erasmus Medical Center, Rotterdam, Netherlands.
    Lexmond, P.
    Department of Virology, Erasmus Medical Center, Rotterdam, Netherlands.
    Waldenstrom, J.
    Waldenström, J., Section for Zoonotic Ecology and Epidemiology, Department of Biology and Environmental Science, University of Kalmar, Kalmar, Sweden.
    Wallensten, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Fransson, T.
    Bird Ringing Center, Swedish Museum of Natural History, Stockholm, Sweden.
    Rimmelzwaan, G.F.
    Department of Virology, Erasmus Medical Center, Rotterdam, Netherlands.
    Beyer, W.E.P.
    Department of Virology, Erasmus Medical Center, Rotterdam, Netherlands.
    Schutten, M.
    Department of Virology, Erasmus Medical Center, Rotterdam, Netherlands.
    Olsen, B.
    Section for Zoonotic Ecology and Epidemiology, Department of Biology and Environmental Science, University of Kalmar, Kalmar, Sweden, Department of Clinical Science, Uppsala University Hospital, Uppsala, Sweden.
    Osterhaus, A.D.M.E.
    Department of Virology, Erasmus Medical Center, Rotterdam, Netherlands.
    Fouchier, R.A.M.
    Department of Virology, Erasmus Medical Center, Rotterdam, Netherlands.
    Spatial, temporal, and species variation in prevalence of influenza a viruses in wild migratory birds2007In: PLoS Pathogens, ISSN 1553-7366, Vol. 3, no 5, p. 0630-0638Article in journal (Refereed)
    Abstract [en]

    Although extensive data exist on avian influenza in wild birds in North America, limited information is available from elsewhere, including Europe. Here, molecular diagnostic tools were employed for high-throughput surveillance of migratory birds, as an alternative to classical labor-intensive methods of virus isolation in eggs. This study included 36,809 samples from 323 bird species belonging to 18 orders, of which only 25 species of three orders were positive for influenza A virus. Information on species, locations, and timing is provided for all samples tested. Seven previously unknown host species for avian influenza virus were identified: barnacle goose, bean goose, brent goose, pink-footed goose, bewick's swan, common gull, and guillemot. Dabbling ducks were more frequently infected than other ducks and Anseriformes, this distinction was probably related to bird behavior rather than population sizes. Waders did not appear to play a role in the epidemiology of avian influenza in Europe, in contrast to the Americas. The high virus prevalence in ducks in Europe in spring as compared with North America could explain the differences in virus-host ecology between these continents. Most influenza A virus subtypes were detected in ducks, but H13 and H16 subtypes were detected primarily in gulls. Viruses of subtype H6 were more promiscuous in host range than other subtypes. Temporal and spatial variation in influenza virus prevalence in wild birds was observed, with influenza A virus prevalence varying by sampling location, this is probably related to migration patterns from northeast to southwest and a higher prevalence farther north along the flyways. We discuss the ecology and epidemiology of avian influenza A virus in wild birds in relation to host ecology and compare our results with published studies. These data are useful for designing new surveillance programs and are particularly relevant due to increased interest in avian influenza in wild birds. © 2007 Munster et al.

  • 64.
    Nilsson, M.
    et al.
    Department of Virology, Swed. Inst. for Infect. Dis. Control, 171 82 Solna, Sweden, Ctr. for Microbiol. Preparedness, Swed. Inst. for Infect. Dis. Control, 171 82 Solna, Sweden.
    Hedlund, K.-O.
    Department of Virology, Swed. Inst. for Infect. Dis. Control, 171 82 Solna, Sweden.
    Thorhagen, M.
    Department of Virology, Swed. Inst. for Infect. Dis. Control, 171 82 Solna, Sweden.
    Larson, G.
    Dept. of Clin. Chem./Transfus. Med., Sahlgenska University Hospital, 413 45 Göteborg, Sweden.
    Johansen, K.
    Department of Virology, Swed. Inst. for Infect. Dis. Control, 171 82 Solna, Sweden.
    Ekspong, A.
    Department of Medicine, Sundsvall County Hospital, 851 86 Sundsvall, Sweden.
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Evolution of Human Calicivirus RNA in Vivo: Accumulation of Mutations in the Protruding P2 Domain of the Capsid Leads to Structural Changes and Possibly a New Phenotype2003In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 77, no 24, p. 13117-13124Article in journal (Refereed)
    Abstract [en]

    In the present study we report on evolution of calicivirus RNA from a patient with chronic diarrhea (i.e., lasting >2 years) and viral shedding. Partial sequencing of open reading frame 1 (ORF1) from 12 consecutive isolates revealed shedding of a genogroup II virus with relatively few nucleotide changes during a 1-year period. The entire capsid gene (ORF2) was also sequenced from the same isolates and found to contain 1,647 nucleotides encoding a protein of 548 amino acids with similarities to the Arg320 and Mx strains. Comparative sequence analysis of ORF2 revealed 32 amino acid changes during the year. It was notable that the vast majority of the cumulative amino acid changes (8 of 11) appeared within residues 279 to 405 located within the hypervariable domain (P2) of the capsid protein and hence were subject to immune pressure. An interesting and novel observation was that the accumulated amino acid changes in the P2 domain resulted in predicted structural changes, including disappearance of a helix structure, and thus a possible emergence of a new phenotype. FUT2 gene polymorphism characterization revealed that the patient is heterozygous at nucleotide 428 and thus Secretor+, a finding in accordance with the hypothesis of FUT2 gene polymorphism and calicivirus susceptibility. To our knowledge, this is the first report of RNA evolution of calicivirus in a single individual, and our data suggest an immunity-driven mechanism for viral evolution. We also report on chronic virus excretion, immunoglobulin treatment, and modification of clinical symptoms, our observations from these studies, together with the FUT2 gene characterization, may lead to a better understanding of calicivirus pathogenesis.

  • 65.
    Nitiema, Leon W
    et al.
    University of Ouagadougou.
    Nordgren, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Ouermi, Djeneba
    University of Ouagadougou.
    Dianou, Dayeri
    Centre for National Resarch Science and Technology, Ouagadougou.
    Traore, Alfred S
    University of Ouagadougou.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Simpore, Jacques
    University of Ouagadougou.
    Burden of rotavirus and other enteropathogens among children with diarrhea in Burkina Faso2011In: International Journal of Infectious Diseases, ISSN 1201-9712, E-ISSN 1878-3511, Vol. 15, no 9, p. E646-E652Article in journal (Refereed)
    Abstract [en]

    Objective: There is limited information available regarding the etiology of gastrointestinal infections in Burkina Faso. The aim of this study was to investigate the prevalence and epidemiology of enteric pathogens causing gastroenteritis in young children, with a focus on rotavirus, and to investigate the levels of malnutrition and other clinical factors in association with the severity of diarrhea. less thanbrgreater than less thanbrgreater thanMethods: A prospective study was undertaken from May 2009 to March 2010, covering the rainy and dry seasons, at the Saint Camille Medical Center in Ouagadougou, Burkina Faso. A total of 309 children less than 5 years of age with diarrhea were enrolled and examined for rotavirus, bacterial, and parasitic infections, as well as clinico-epidemiological aspects. less thanbrgreater than less thanbrgreater thanResults: At least one enteropathogen was detected in 57.9% (n = 179) of the children. Of these, 32.4% had rotavirus infections, 16.8% bacterial infections (enteropathogenic Escherichia coli 9.7%, Shigella spp 5.8%, and Salmonella spp 2.3%), and 18.8% parasitic infections (Giardia lamblia 11.3%, Trichomonas intestinalis 6.8%, Entamoeba histolytica/dispar 1.3%). During the cold dry period from December 2009 to February 2010, we observed a large increase in diarrhea cases, which was mainly attributed to rotavirus infections, as 63.8% of these diarrhea cases were positive for rotavirus. In contrast, no rotavirus infection was observed during the rainy season (June-September 2009), when the frequency of parasitic infections was high. Rotavirus and parasitic infections were age-related, with rotavirus being more prevalent in young children (andlt;12 months) and parasites more common in older children (andgt;12 months), while bacteria were equally prevalent among all age groups. Rotavirus infections exhibited more severe symptoms compared to bacteria and parasites, and were associated with fever, vomiting, and severe dehydration. Malnutrition, especially acute malnutrition (wasting), was significantly associated with more severe symptoms in rotavirus-induced diarrhea. The undernourished children also exhibited a prolonged duration of diarrheal episodes. less thanbrgreater than less thanbrgreater thanConclusion: This study demonstrates rotavirus as the main etiological agent in pediatric diarrhea in Burkina Faso, and further shows the great severity of rotavirus-induced diarrhea in undernourished children in Burkina Faso.

  • 66.
    Nordgren, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Bucardo, Filemon
    Department of Microbiology, University of León, León, Nicaragua.
    Dienus, Olaf
    Microbiological Laboratory, Ryhov County Hospital, Jönköping, Sweden.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Lindgren, Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Correction: Novel Light-Upon-Extension Real-Time PCR Assays for Detection and Quantification of Genogroup I and II Noroviruses in Clinical Specimens (vol 46, pg 164, 2008)2009In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 47, no 4, p. 1285-1285Article in journal (Other academic)
  • 67.
    Nordgren, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Bucardo, Filemon
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Lindgren, Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Novel Light-Upon-Extension Real-Time PCR Assay for Simultaneous Detection, Quantification, and Genogrouping of Group A Rotavirus2010In: JOURNAL OF CLINICAL MICROBIOLOGY, ISSN 0095-1137, Vol. 48, no 5, p. 1859-1865Article in journal (Refereed)
    Abstract [en]

    We have developed a light-upon-extension (LUX) real-time PCR assay for detection, quantification, and genogrouping of group A rotavirus (RV), the most common cause of acute gastroenteritis in children. The LUX system uses a fluorophore attached to one primer and having a self-quenching hairpin structure, making it cost-effective and specific. We designed genogroup-specific primers having different fluorophores, making it possible to differentiate between the two main genogroups of human group A RVs. The assay was applied on clinical stool specimens from Sweden and Central America (n = 196) and compared to immunological and conventional PCR assays. The genogrouping ability was further validated against a subset of clinical specimens, which had been genogrouped using monoclonal antibodies. Our real-time PCR assay detected and quantified all positive specimens (n = 145) and exhibited higher sensitivity than immunological assays and conventional PCR. The assay exhibited a wide dynamic range, detecting from 5 to andgt; 10(7) genes per PCR, resulting in a theoretical lower detection limit of andlt; 10,000 viruses per gram of stool. No cross-reaction was observed with specimens containing norovirus, sapovirus, astrovirus, or adenovirus. In total, 22 (15%) of the positive clinical specimens were identified as genogroup I, 122 (84%) were identified as genogroup II, and 1 specimen was found to contain a mix of both genogroups. All genogroup I-positive specimens were associated with capsid glycoprotein 2 (G2). No significant difference in viral load was found between genogroups or geographic region. The detection and quantification, combined with the genogrouping ability, make this assay a valuable tool both for diagnostics and for molecular epidemiological investigations.

  • 68.
    Nordgren, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Bucardo, Filemón
    Department of Microbiology, University of León, León, Nicaragua.
    Dienus, Olaf
    Microbiological Laboratory, Ryhov County Hospital, Jönköping, Sweden.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Lindgren, Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Novel light-upon-extension real-time PCR assays for detection and quantification of genogroup I and II noroviruses in clinical specimens2008In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 46, no 1, p. 164-170Article in journal (Refereed)
    Abstract [en]

    Norovirus is now recognized as the leading cause of nonbacterial acute gastroenteritis in adults, causing numerous outbreaks worldwide. We have developed two novel light-upon-extension (LUX) real-time PCR assays for detection and quantification of norovirus genogroups I and II. The LUX system uses a fluorophore attached to one primer having a self-quenching hairpin structure, making it cost-effective and specific. The assays were evaluated against clinical stool specimens (n = 103) from Sweden and Nicaragua and compared to established methods. The norovirus assay detected more positive stool specimens (47/103) than conventional PCR (39/103) and corresponded to a TaqMan real-time PCR, with the exception of one specimen. Furthermore, the assays correctly identified all (n = 11) coded control specimens in a reference panel containing various genogroups and genotypes. Both LUX real-time PCR assays had a wide dynamic range, detecting from < or = 10(1) to 10(7) genes per reaction, resulting in a theoretical lower limit of < or = approximately 20,000 viruses per gram of stool. No cross-reactivity was noticed with specimens containing other enteric viruses, and by using melting curve analysis we could differentiate between norovirus genogroups I and II.

  • 69.
    Nordgren, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Juste O Bonkoungou, Isidore
    Laboratoire National de Santé Publique du Burkina Faso, Ouagadougou, Burkina Faso, Laboratoire de Biologie Moléculaire, d’Epidémiologie et Surveillance des Bactéries et Virus Transmissibles par les Aliments, CRSBAN/UFR-SVT, Université de Ouagadougou, Ouagadougou, Burkina Faso.
    Nitiema, Leon W.
    Centre de Recherche Biomoléculaire Pietro Annigoni, Saint Camille CERBA/LABIOGENE, Université de Ouagadougou, Ouagadougou, Burkina Faso, Centre de Recherche en Sciences Biologiques, Alimentaires et Nutritionnelles (CRSBAN), Université de Ouagadougou, Ouagadougou, Burkina Faso.
    Sharma, Sumit
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Ouermi, Djeneba
    Centre de Recherche Biomoléculaire Pietro Annigoni, Saint Camille CERBA/LABIOGENE, Université de Ouagadougou, Ouagadougou, Burkina Faso.
    Simpore, Jacques
    Centre de Recherche Biomoléculaire Pietro Annigoni, Saint Camille CERBA/LABIOGENE, Université de Ouagadougou, Ouagadougou, Burkina Faso.
    Barro, Nicolas
    Laboratoire de Biologie Moléculaire, d’Epidémiologie et Surveillance des Bactéries et Virus Transmissibles par les Aliments, CRSBAN/UFR-SVT, Université de Ouagadougou, Ouagadougou, Burkina Faso.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Rotavirus in diarrheal children in rural Burkina Faso: High prevalence of genotype G6P[6]2012In: Infection, Genetics and Evolution, ISSN 1567-1348, E-ISSN 1567-7257, Vol. 12, no 8, p. 1892-1898Article in journal (Refereed)
    Abstract [en]

    Group A rotavirus (RVA) is the most common cause of severe gastroenteritis in young children globally, and responsible for a significant number of deaths in African countries. While vaccines are available, trials have shown a lesser efficacy in Africa. One of the reasons could be the prevalence and/or emergence of unusual or novel RVA strains, as many strains detected in African countries remain uncharacterized. less thanbrgreater than less thanbrgreater thanIn this study, we characterized RVA positive specimens from two remote rural areas in Burkina Faso, West Africa. In total 56 RVA positive specimens were subgrouped by their VP6 gene, and G-and P typed by PCR and/or sequencing of the VP7 and VP4 genes, respectively. less thanbrgreater than less thanbrgreater thanNotably, we found a high prevalence of the unusual G6P[6]SGI strains (23%). It was the second most common constellation after G9P[8]SGII (32%); and followed by G1P[8]SGII (20%) and G2P[4]SGI (9%). We also detected a G8P[6]SGI strain, for the first time in Burkina Faso. The intra-genetic diversity was high for the VP4 gene with two subclusters within the P[8] genotype and three subclusters within the P[6] genotype which were each associated with a specific G-type, thereby suggesting a genetic linkage. The G6P[6]SGI and other SGI RVA strains infected younger children as compared to SGII strains (p andlt; 0.05). less thanbrgreater than less thanbrgreater thanTo conclude, in this study we observed the emergence of unusual RVA strains and high genetic diversity of RVA in remote rural areas of Burkina Faso. The results highlight the complexity of RVA epidemiology which may have implication for the introduction of rotavirus vaccines currently being evaluated in many African countries.

  • 70.
    Nordgren, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Kindberg, Elin
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Lindgren, Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Matussek, Andreas
    Department of Clinical Microbiology, Division of Laboratory Medicine, County Hospital Ryhov, Jönköping, Sweden/Department of Clinical Microbiology, Capio Diagnostik AB, Capio St Görans Hospital, Stockholm, Sweden.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    A FUT2 nonsense mutation (G428A) and Lewis-independent norovirus GI.3 outbreak2009Article in journal (Other academic)
    Abstract [en]

    Background: Norovirus (NoV) is recognized as the commonest cause of acute gastroenteritis among adults. Previous studies have shown that histo-blood group antigens (HBGAs) and secretor status are associated with susceptibility to symptomatic NoV infection, with non-secretors being almost completely resistant to disease. Here we report on a food-borne GI.3 NoV outbreak affecting 33/83 (40%) individuals.

    Methods: Secretor status and HBGA expression in saliva were determined with pyrosequencing and ELISA. Virus characterization was performed by sequencing the N/S region and the complete capsid gene.

    Results: A novel observation was that homozygous carriers of the nonsense FUT2 G428A allele were more susceptible to symptomatic infection than secretors (odds ratio [OR] 1.41 vs 0.71). Consistent with this observation was that Lewis a positive b negative (Lea+b-) individuals showed the highest susceptibility (OR 2.42) compared with other Lewis phenotypes. Blood group B was associated with partial protection (OR 0.27). The capsid gene of the outbreak strain exhibits high amino acid homology with the Kashiwa645 GI.3 strain, previously shown to recognize non-secretor saliva.

    Conclusion: We describe for the first time a NoV outbreak with Lea+b- individuals homozygous for the G428A nonsense mutation in the FUT2 gene being more susceptible for disease than secretor-positive individuals.

  • 71.
    Nordgren, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Lindgren, Per-Eric
    County Hospital Ryhov, Jonkoping, Sweden .
    Matussek, Andreas
    County Hospital Ryhov, Jonkoping, Sweden Capio St Gorans Hospital, Stockholm, Sweden .
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Norovirus Gastroenteritis Outbreak with a Secretor-independent Susceptibility Pattern, Sweden2010In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 16, no 1, p. 81-87Article in journal (Refereed)
    Abstract [en]

    Norovirus (NoV) is recognized as the commonest cause of acute gastroenteritis among adults. Susceptibility to disease has been associated with histo-blood group antigens and secretor status; nonsecretors are almost completely resistant to disease. We report a foodborne outbreak of GI.3 NoV gastroenteritis that affected 33/83 (40%) persons. Symptomatic disease was as likely to develop in nonsecretors as in secretors (odds ratio [OR] 1.41, 95% confidence interval [CI] 0.46-4.36 vs. OR 0.71, 95% Cl 0.23-2.18, p = 0.57). Moreover, no statistical difference in susceptibility was found between persons of different Lewis or ABO phenotypes. The capsid gene of the outbreak strain shares high amino acid homology with the Kashiwa645 GI.3 strain, previously shown to recognize nonsecretor saliva, as well as synthetic Lewis a. This norovirus outbreak affected persons regardless of secretor status or Lewis or ABO phenotypes.

  • 72.
    Nordgren, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Matussek, Andreas
    Department of Clinical Microbiology, County Hospital Ryhov, 55185 Jönköping, Sweden.
    Mattsson, Ann
    Gryaab AB, Gothenburg, Sweden.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Lindgren , Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Prevalence of norovirus and factors influencing virus concentrations during one year in a full-scale wastewater treatment plant2009In: Water Research, ISSN 0043-1354, E-ISSN 1879-2448, Vol. 43, no 4, p. 1117-1125Article in journal (Refereed)
    Abstract [en]

    Norovirs (NoV) is a leading cause of acute gastroenteritis and is often spread via wastewater contamination. Little is known about how the wastewater treatment process affects norovirus, and which factors influence virus concentrations. To investigate this, we collected wastewater samples monthly during one year at eight different key sites at the municipal wastewater treatment plant in Gothenburg, Sweden. Virus particles were concentrated using ultracentrifugation, viral RNA was subsequently extracted, and transformed into cDNA by reverse transcription. The quantification was performed with real-time PCR assays for NoV genogroups I (GGI) and II (GGII), respectively. We found seasonal changes of NoV genogroups, with the highest concentration of NoV GGII during the winter months, and the highest concentration of NoV GGI during the summer months. Virus transmission in wastewater was more stable for NoV GGI, with NoV GGII demonstrating larger seasonal peaks. Virus reduction took place at similar rates in the primary settling, and in the activated sludge in combination with the secondary settling. Different physicochemical parameters and incoming virus concentrations were correlated to reduction of NoV between different treatment sites. This study gives new information about NoV transmission and virus reduction in a wastewater treatment plant.

  • 73.
    Nordgren, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Nitiema, Leon W
    University of Ouagadougou.
    Sharma, Sumit
    University of Ouagadougou.
    S Traore, Alfred
    University of Ouagadougou.
    Simpore, Jacques
    University of Ouagadougou.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Emergence of Unusual G6P[6] Rotaviruses in Children, Burkina Faso, 2009-20102012In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 18, no 4, p. 589-597Article in journal (Refereed)
    Abstract [en]

    To obtain more information about rotavirus (ROTAV) genotypes in Burkina Faso, we characterized 100 ROTAVs isolated from fecal samples of children with acute gastroenteritis in the capital city of Ouagadougou, during December 2009 March 2010. Of note, 13% of the ROTAV-positive samples, including those with mixed infections, were positive for the unusual G6 genotype ROTAV strain. The genotypes identified were G9P[8], G6P[6], G1P[6], G3P[6], G1P[8], and G2P[4]. G9P[8] subgroup (SG) II strains dominated during the beginning of the ROTAV season, but later in the season, other G types associated with P[6] and SGI specificity emerged. This emergence was related to a shift in the overall age of infected children; ROTAV SGII infected younger children and induced more severe symptoms. The finding of a high incidence of G6P[6] strains highlights the need for long-term surveillance of ROTAV strains in Burkina Faso, especially when ROTAV vaccination is being considered in several African countries.

  • 74. Nygard, K
    et al.
    Torven, M
    Ancker, C
    Knauth, SB
    Hedlund, KO
    Giesecke, J
    Andersson, Y
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Emerging genotype (GGIIb) of norovirus in drinking water, Sweden2003In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 9, no 12, p. 1548-1552Article in journal (Refereed)
    Abstract [en]

    From May through June 2001, an outbreak of acute gastroenteritis that affected at least 200 persons occurred in a combined activity camp and conference center in Stockholm County. The source of illness was contaminated drinking water obtained from private wells. The outbreak appears to have started with sewage pipeline problems near the kitchen, which caused overflow of the sewage system and contaminated the environment. While no pathogenic bacteria were found in water or stools specimens, norovirus was detected in 8 of 11 stool specimens and 2 of 3 water samples by polymerase chain reaction. Nucleotide sequencing of amplicons from two patients and two water samples identified an emerging genotype designated GGIIb, which was circulating throughout several European countries during 2000 and 2001. This investigation documents the first waterborne outbreak of viral gastroenteritis in Sweden, where nucleotide sequencing showed a direct link between contaminated water and illness.

  • 75.
    Nystrom, Sanna
    et al.
    Centre Infect Med, Stockholm.
    Brave, Andreas
    Karolinska Institute.
    Rissiek, Bjorn
    University of Hamburg Hospital.
    Johansson, Daniel X
    Karolinska Institute.
    Schroder, Ulf
    Eurocine Vaccines AB.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Applequist, Steven E
    Centre Infect Med, Stockholm.
    DNA-Encoded Flagellin as an Epidermal, Systemic, and Mucosal-Adjuvant in SCANDINAVIAN JOURNAL OF IMMUNOLOGY, vol 73, issue 4, pp 393-3932011In: SCANDINAVIAN JOURNAL OF IMMUNOLOGY, Blackwell Publishing Ltd , 2011, Vol. 73, no 4, p. 393-393Conference paper (Refereed)
    Abstract [en]

    n/a

  • 76.
    Olsen, Björn
    et al.
    Department of Infectious Diseases, Umeå University, Umeå, Sweden.
    Munster, Vincent J.
    Department of Virology, Erasmus Medical Center, Rotterdam, Netherlands..
    Wallensten, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Waldenström, Jonas
    Department of Animal Ecology, Lund University, Lund, Sweden..
    Osterhaus, Albert D. M. E.
    Department of Virology, Erasmus Medical Center, Rotterdam, Netherlands..
    Fouchier, Ron A.M.
    Department of Virology, Erasmus Medical Center, Rotterdam, Netherlands..
    Global patterns of influenza A virus in wild birds2006In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 312, no 5772, p. 384-388Article in journal (Refereed)
    Abstract [en]

    The outbreak of highly pathogenic avian influenza of the H5N1 subtype in Asia, which has subsequently spread to Russia, the Middle East, Europe, and Africa, has put increased focus on the role of wild birds in the persistence of influenza viruses. The ecology, epidemiology, genetics, and evolution of pathogens cannot be fully understood without taking into account the ecology of their hosts. Here, we review our current knowledge on global patterns of influenza virus infections in wild birds, discuss these patterns in the context of host ecology and in particular birds' behavior, and identify some important gaps in our current knowledge.

  • 77.
    Oluwatoyin Japhet, Margaret
    et al.
    Obafemi Awolowo University, Nigeria .
    Adeyemi Adesina, Olufisayo
    Obafemi Awolowo University, Nigeria .
    Famurewa, Oladiran
    Ekiti State University, Nigeria .
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Nordgren, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Molecular epidemiology of rotavirus and norovirus in Ile-Ife, Nigeria: High prevalence of G12P[8] rotavirus strains and detection of a rare norovirus genotype2012In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 84, no 9, p. 1489-1496Article in journal (Refereed)
    Abstract [en]

    Rotavirus (RV) and norovirus (NoV) are considered the most common causes of viral gastroenteritis in children. In this study, the prevalence of RV and NoV infection in 55 children with diarrhea from the rural community Akinlalu in Southwestern Nigeria was investigated using real-time PCR assays. The RV and NoV strains were genotyped by PCR and/or sequencing. RV and NoV infections occurred with a prevalence of 34.5% and 25.5% respectively, with predominance in children andlt;1 year. Most infections occurred during the dry season with increasing prevalence of RV as the dry season progressed (OctoberJanuary). Infections with RV VP6 subgroup (SG) II were more prevalent (27.3%) than SGI (7.3%). Similarly, NoV genogroup II infections were more common (23.6%) than genogroup I (1.8%). Five children out of 55 (9.1%) were co-infected with both RV and NoV. Notably, G12P[8] was the predominant RV strain (36.8%, n?=?7), observed for the first time in Nigeria. The VP7 gene of the G12 strains clustered within lineage III, sharing high nucleotide identity with each other (andgt;99%) indicating introduction in Nigeria from a single donor. Furthermore, a putative novel genotype within genogroup I NoV was detected, which till date has only been reported once in humans. To conclude, a high prevalence of the emerging G12P[8] RV strain was observed for the first time in Nigeria, as well as a putative novel NoV genotype in humans. These results provide new information which can be important for future vaccine evaluations and possible introduction in Nigeria.

  • 78.
    Pant, N.
    et al.
    Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.
    Marcotte, H.
    Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.
    Brussow, H.
    Brüssow, H., Nutrition and Health Department, Food and Health Microbiology, Nestlé Research Centre, CH-1000 Lausanne, Switzerland.
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Hammarstrom, L.
    Hammarström, L., Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.
    Effective prophylaxis against rotavirus diarrhea using a combination of Lactobacillus rhamnosus GG and antibodies2007In: BMC Microbiology, ISSN 1471-2180, E-ISSN 1471-2180, Vol. 7Article in journal (Refereed)
    Abstract [en]

    Background. Rotavirus is a worldwide cause of infectious infantile diarrhea that claims over 600,000 lives annually. Recently, two new vaccine candidates have been developed but their efficacy in developing countries, still remains to be proven. Oral delivery of specific immunoglobulins provides passive immunity and is a fast acting treatment for rotavirus diarrhea. Probiotic bacteria have also gained considerable attention lately as treatment for rotavirus diarrhea. Here we report an evaluation of the therapeutic potential of different probiotics and their combination with anti - rotavirus antibodies in a mouse model of rotavirus diarrhea. Results. Of the six probiotic bacteria tested, Lactobacillus rhamnosus strain GG had the strongest influence in reducing prevalence, duration and severity of diarrhea and was therefore chosen for combination treatment with immunoglobulins. The combination treatment reduced the diarrhea outcome measures significantly, prevented histopathological changes and reduced the virus load in the intestines. Conclusion. The advantages associated with immunoglobulins and probiotics based therapy is that the treatment provides a rapid therapeutic effect and is cost efficient. These components do not require special storage conditions and could potentially complement the rehydration therapy that is currently used. © 2007 Pant et al, licensee BioMed Central Ltd.

  • 79.
    Rodriguez, Jesus
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Rubilar-Abreu, Elba
    Swedish Institute for Infectious Disease Control Solna.
    Spitzner, Markus
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Hedlund, Kjell-Olof
    Swedish Institute for Infectious Disease Control Solna.
    Liprandi, Ferdinando
    Center for Microbiology and Cell Biology Venezuelan Institute for Scientific Research, Caracas, Venezuela.
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Design of a multiplex nested PCR for genotyping of the NSP4 from group A rotavirus2008In: Journal of Virological Methods, ISSN 0166-0934, E-ISSN 1879-0984, Vol. 149, no 2, p. 240-245Article in journal (Refereed)
    Abstract [en]

    A novel PCR method was developed to discriminate amongst genotypes A-C of the rotavirus non-structural protein 4 (NSP4). Genotype-specific primers were designed that correctly identified the NSP4 genotype when evaluated as a multiplex PCR with cell culture adapted rotavirus strains. Rotavirus strains B223 SGIG6P6[1], NCDV SGIG6P6[1] and SA11 SGIG3P5B[2] were used as control for NSP4 genotype A, A34 SGIG5P14[23], Gottfried SGIIG4P2B[6] and Wa SGIIG1P1A[8] for NSP4 genotype B, RRV SGIG3P5B[3] for NSP4 genotype C. Subsequently, the same set of specific primers was used to genotype a set of 77 Swedish clinical samples. The results showed that all human clinical samples analyzed belong to the NSP4 genotype B and the VP6 subgroup II. © 2008 Elsevier B.V. All rights reserved.

  • 80.
    Rydell, Gustaf E
    et al.
    University of Gothenburg.
    Kindberg, Elin
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Larson, Goeran
    University of Gothenburg.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Susceptibility to winter vomiting disease: a sweet matter2011In: Reviews in Medical Virology, ISSN 1052-9276, E-ISSN 1099-1654, Vol. 21, no 6, p. 370-382Article, review/survey (Refereed)
    Abstract [en]

    Norovirus, the cause of winter vomiting disease, has emerged in recent years to be a major cause of sporadic and epidemic gastroenteritis worldwide. The virus has been estimated to cause andgt;200 000 deaths each year in developing countries. Although the virus is highly contagious, volunteer and field studies have shown that a subset of individuals appears resistant to infections. A single nucleotide mutation (G428A) in the fucosyltransferase gene (FUT2) on chromosome 19 provides strong protection from infection in 20% of the white population. Histo-blood group ABO(H) antigens with terminal fucose are believed to function as receptors for human norovirus in the gastrointestinal tract, but also negatively charged potential receptors have been identified. Norovirus infection is a unique example where a single nucleotide mutation in a fucosyltransferase gene plays a crucial role in susceptibility to one of the most common viral diseases. This review discusses the role of host genetics and carbohydrate structures in susceptibility to winter vomiting disease.

  • 81.
    Rydell, Gustaf E
    et al.
    Sahlgrens University Hospital.
    Nilsson, Jonas
    Sahlgrens University Hospital.
    Rodriguez, Jesus
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Ruvoen-Clouet, Nathalie
    INSERM.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Le Pendu, Jacques
    INSERM.
    Larson , Goran
    Sahlgrens University Hospital.
    Human noroviruses recognize sialyl Lewis x neoglycoprotein2009In: Glycobiology, ISSN 0959-6658, E-ISSN 1460-2423, Vol. 19, no 3, p. 309-320Article in journal (Refereed)
    Abstract [en]

    The carbohydrate binding characteristics of a norovirus GII.3 (Chron1) and a GII.4 (Dijon) strain were investigated using virus-like particles (VLPs) and saliva samples from 81 individuals genotyped for FUT2 (secretor) and FUT3 (Lewis) and phenotyped for ABO and Lewis blood groups. The two VLPs showed a typical secretor-gene-dependent binding and bound significantly stronger to saliva from A, B, and AB than from O individuals (P < 0.0001 and P < 0.001) but did not bind to any samples from secretor-negative individuals. The GII.3 strain showed larger interindividual variation and bound stronger to saliva from B than from A(2) secretors (P < 0.01). When assaying for binding to neoglycoproteins, the GII.3 and GII.4 strains were compared with the Norwalk GI.1 prototype strain. Although all three strains bound to Lewis b (and H type 1 chain) glycoconjugates, only the two GII strains showed an additional binding to sialyl Lewis x. This novel binding was specific since the VLPs did not bind to structural analogs, e.g., Lewis x or sialyl Lewis a, but only to sialyl Lewis x, sialyl diLewis x and sialylated type 2 chain conjugates. In inhibition experiments, the sialyl Lewis x conjugate was the most potent inhibitor. The minimal requirement for this potential receptor structure is Neu5Ac alpha 3Gal beta 4(Fuc alpha 3)GlcNAc beta 3Gal beta- where Fuc is not absolutely necessary for binding. Our study shows that some human norovirus GII strains have at least two binding specificities: one secretor-gene-dependent related to alpha 1,2-fucosylated carbohydrates and another related to alpha 2,3-sialylated carbohydrates of the type 2 chain, e.g., sialyl Lewis x.

  • 82.
    Sabado, Rachel L.
    et al.
    Department of Medicine and Pathology, School of Medicine, New York University, New York, NY, United States.
    Babcock, Ethan
    Department of Medicine and Pathology, School of Medicine, New York University, New York, NY, United States.
    Kavanagh, Daniel G.
    Department of Medicine and Pathology, School of Medicine, New York University, New York, NY, United States, Partner AIDS Research Center, Massachusetts General Hospital, Charlestown, MA, United States.
    Tjomsland, Veronica
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Walker, Bruce D.
    Partner AIDS Research Center, Massachusetts General Hospital, Charlestown, MA, United States, Howard Hughes Medical Institute, Chevy Chase, MD, United States.
    Lifson, Jeffrey D.
    AIDS Vaccine Program, SAIC-Frederick Inc., National Cancer Institute at Frederick, Frederick, MD, United States.
    Bhardwaj, Nina
    Department of Medicine and Pathology, School of Medicine, New York University, New York, NY, United States.
    Larsson, Marie
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology.
    Pathways utilized by dendritic cells for binding, uptake, processing and presentation of antigens derived from HIV-12007In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 37, no 7, p. 1752-1763Article in journal (Refereed)
    Abstract [en]

    The outcome following HIV infection depends on the nature and durability of the HIV-specific T cell response induced initially. The activation of protective T cell responses depends upon dendritic cells (DC), antigen-presenting cells which have the capacity to process and present viral antigens. DC pulsed with aldrithiol-2-inactivated HIV and delivered in vivo were reported to induce immune responses and promote virologic control in chronically HIV-1-infected subjects. To gain an understanding of this phenomenon, we characterized the steps involved in the presentation of antigens derived from aldrithiol-2-treated vs. infectious HIV-1 by DC. Antigen presentation, on both MHC class I and II, was independent of DC-specific ICAM-3-grabbing integrin, DEC-205 and macrophage mannose receptor, C-type lectins expressed by the DC. Inhibitor studies showed that presentation on MHC class I was dependent on viral fusion in a CD4/coreceptor-dependent manner, both at the cell surface and within endosomes, and access to the classical endosomal processing pathway. MHC class II presentation of HIV-associated antigens was dependent on active endocytosis, probably receptor-mediated, and subsequent degradation of virions in acidified endosomes in the DC. Our study brings forth new facts regarding the binding, uptake, and processing of chemically inactivated virions leading to efficient antigen presentation and should aid in the design of more effective HIV vaccines. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  • 83.
    Sabado, R.L.
    et al.
    New York University School of Medicine.
    Kavanagh, D.G.
    Partners AIDS Research Center.
    Kaufmann, D.E.
    Partners AIDS Research Center.
    Fru Che, Karlhans
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Babcock, E.
    New York University School of Medicine.
    Rosenberg, E.
    Partners AIDS Research Center.
    Walker, B.
    Partners AIDS Research Center.
    Lifson, J.
    SAIC Fredrick, Inc..
    Bhardwaj, N.
    New York University School of Medicine.
    Larsson , Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    In vitro priming recapitulates in vivo HIV-1 specific T cell responses, revealing rapid loss of virus reactive CD4+ T cells in acute HIV-1 infection2009In: PLoS ONE, ISSN 1932-6203, Vol. 4, no 1, p. e4256-Article in journal (Refereed)
    Abstract [en]

    Background: The requirements for priming of HIV-specific T cell responses initially seen in infected individuals remain to be defined. Activation of T cell responses in lymph nodes requires cell-cell contact between T cells and DCs, which can give concurrent activation of T cells and HIV transmission. Methodology: The study aim was to establish whether DCs pulsed with HIV-1 could prime HIV-specific T cell responses and to characterize these responses. Both infectious and aldrithiol-2 inactivated noninfectious HIV-1 were compared to establish efficiencies in priming and the type of responses elicited. Findings: Our findings show that both infectious and inactivated HIV-1 pulsed DCs can prime HIV-specific responses from na�ve T cells. Responses included several CD4+ and CD8+ T cell epitopes shown to be recognized in vivo by acutely and chronically infected individuals and some CD4+ T cell epitopes not identified previously. Follow up studies of acute and recent HIV infected samples revealed that these latter epitopes are among the earliest recognized in vivo, but the responses are lost rapidly, presumably through activation-induced general CD4+ T cell depletion which renders the newly activated HIV-specific CD4+ T cells prime targets for elimination. Conclusion: Our studies highlight the ability of DCs to efficiently prime na�ve T cells and induce a broad repertoire of HIV-specific responses and also provide valuable insights to the pathogenesis of HIV-1 infection in vivo.

  • 84.
    Saenz, R
    et al.
    University of California.
    da Silva Souza, C
    University of Sao Paulo.
    Huang, C-T
    University of California.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Esener, S
    University of California.
    Messmer, D
    University of California.
    HMGB1-derived peptide acts as adjuvant inducing immune responses to peptide and protein antigen2010In: VACCINE, ISSN 0264-410X, Vol. 28, no 47, p. 7556-7562Article in journal (Refereed)
    Abstract [en]

    There is a need for new adjuvants that will induce immune responses to subunit vaccines. We show that a short peptide, named Hp91, whose sequence corresponds to an area within the endogenous molecule high mobility group box (HMGB1) protein 1 potentiates cellular immune responses to peptide antigen and cellular and humoral immune responses to protein antigen in vivo. Hp91 promoted the in vivo production of the immunomodulatory cytokines, IFN-gamma, TNF-alpha, IL-6, and IL-12 (p70), as well as antigen-specific activation of CD8+ T cells. These results demonstrate the ability of a short immunostimulatory peptide to serve as an adjuvant for subunit vaccines.

  • 85.
    Salim, Sa'ad
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Silva, Manuel A
    McMaster University.
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Andersson, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Perdue, Mary H
    McMaster University.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    CD83(+)CCR7(-) Dendritic Cells Accumulate in the Subepithelial Dome and Internalize Translocated Escherichia coli HB101 in the Peyers Patches of Heal Crohns Disease2009In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 174, no 1, p. 82-90Article in journal (Refereed)
    Abstract [en]

    Recurrent Crohns disease originates with small erosions in the follicle-associated epithelium overlying the Peyers patches. Animal studies have illustrated mucosal immune regulation by dendritic cells located in the subepithelial dome. The aim of this study was to characterize the dendritic cells at this specific site in patients with Crohns disease. Heal tissues were obtained after surgery performed on Crohns patients; ileal samples from noninflammatory bowel disease and ulcerative colitis served as standard and inflammatory controls, respectively. Flow cytometry of isolated intestinal mononuclear cells showed a larger subset of dendritic cells in Crohns samples compared with controls. This finding was corroborated by confocal microscopy, showing enhanced infiltrates of cells positive for the dendritic cell markers, DC-SIGN(+) and CD83(+), in the subepithelial dome. Moreover, the CD83(+) cells in Crohns tissues showed reduced expression of the lymph node migratory receptor, CCR7, possibly contributing to the high numbers of dendritic cells. After exposure to nonpathogenic Escherichia coli in Ussing chambers, dendritic cells in the subepithelial dome of Crohns disease demonstrated increased co-localization with translocated bacteria. Immunohistochemical results revealed that DC-SIGN(+) cells in Crohns tissues were found to express toll-like receptor 4 and produce tumor necrosis factor-a. In conclusion, nonmigrating dendritic cells that accumulate in the subepithelial dome and internalize nonpathogenic bacteria may be important for the onset and perpetuation of mucosal inflammation in Crohns disease.

  • 86.
    Salim, Sa'ad Yislam
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Fru Che, Karlhans
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Söderholm, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery Östergötland.
    T-cell expansion capacity of Dendritic cells isolated from patients wiht Chron's diseaseManuscript (preprint) (Other academic)
    Abstract [en]

    Aphtoid lesions at the follicle-associated epithelium (FAE) are one of the earliest observable signs of recurrent ileal Crohn’s disease (CD). In an earlier study, we found an abnormal accumulation of dendritic cells (DCs) situated beneath the FAE, in the sub-epithelial dome (SED) of patients with CD. These DCs were prone to E.coli uptake. The aim here was to isolate and characterise DCs from patients with CD and determine their functional properties in T-cell expansion. Initially, DCs were isolated from eleal mucosa and blood of 5 CD patients and 5 patients with non-IBD disorders, via magnetic bead separation. DCs were also isolated from blood of 5 patients in long-term remission and 5 healthy volunteers, via FACS sorting and separation. Mixed lymphocyte reaction was performed on the isolated DCs and expansion of T-cells was recorded. DCs that were isolated from blood were also characterised via FACS analysis. DCs from patients with active CD had the tendency of having lower T-cell expansion capacity than DCs from non-IBD controls. The capacity to stimulate T-cells proliferation was restored to similar levels as healthy controls in DCs isolated from patients in remission. However, there was more than 10-fold increase in myeloid (CD11c+) DCs present in the peripheral blood mononuclear cells of CD than in healthy controls. The myeloid DCs were primarily immature (CD83-) and expressed the lymph node migratory receptor CCR7. This population of DCs may be responsible for inducing a tolerogenic or regulatory effect. Our results hint to a complex immune-regulatory mechanism where DCs at different stages of chronic inflammation exert different immune-modulatory effects.

  • 87.
    Shankar, Esakimuthu
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Fru Che, Karlhans
    University of California San Diego.
    Lifson, Jeffrey D
    NCI.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Expression of a Broad Array of Negative Costimulatory Molecules and Blimp-1 in T Cells following Priming by HIV-1 Pulsed Dendritic Cells2011In: MOLECULAR MEDICINE, ISSN 1076-1551, Vol. 17, no 3-4, p. 229-240Article in journal (Refereed)
    Abstract [en]

    Accumulating evidence indicates that immune impairment in persistent viral infections could lead to T-cell exhaustion. To evaluate the potential contribution of induction of negative costimulatory molecules to impaired T-cell responses, we primed naive T cells with mature monocyte-derived dendritic cells (MDDCs) pulsed with HIV-1 in vitro. We used quantitative real-time polymerase chain reaction and flow cytometry, respectively, to compare the gene and surface-protein expression profiles of naive T cells primed with HIV-pulsed or mock-pulsed DCs. We detected elevated expressions of negative costimulatory molecules, including lymphocyte activation gene-3 (LAG-3). CD160, cytolytic T-lymphocyte antigen-4 (CTLA-4). T-cell immunoglobulin mucin-containing domain-3 (TIM-3), programmed death-1 (PD-1) and TRAIL (tumor necrosis-factor-related apoptosis-inducing ligand) in T cells primed by HIV-pulsed DCs. The PD-1(+) T-cell population also coexpressed TIM-3, LAG-3, and CTLA-4. Interestingly, we also found an increase in gene expression of the transcriptional repressors Blimp-1 (B-lymphocyte-induced maturation protein-1) and Foxp3 (forkhead transcription factor) in T-cells primed by HIV-pulsed DCs; Blimp-1 expression was directly proportional to the expression of the negative costimulatory molecules. Furthermore, levels of the effector cytokines interleukin-2, tumor necrosis factor-alpha and interferon-gamma, and perforin and granzyme B were decreased in T-cell populations primed by HIV-pulsed DCs. In conclusion, in vitro priming of halve T-cells with HIV-pulsed DC leads to expansion of T cells with coexpression of a broad array of negative costimulatory mclecules and Blimp-1, with potential deleterious consequences for T-cell responses.

  • 88.
    Timpka, Toomas
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Preventive and Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences.
    Gursky, Elin A
    ANSER/Analytic Services Inc, Arlington, Virginia, USA.
    Spreco, Armin
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Eriksson, Olle
    Linköping University, Department of Computer and Information Science, Statistics. Linköping University, Faculty of Arts and Sciences.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences.
    Strömgren, Magnus
    Umeå University, Sweden.
    Holm, Einar
    Umeå University, Sweden.
    Ekberg, Joakim
    Linköping University, Department of Medical and Health Sciences, Division of Preventive and Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Nyce, Jim M
    Ball State University, Muncie, IN, USA..
    Eriksson, Henrik
    Linköping University, Department of Computer and Information Science, Human-Centered systems. Linköping University, The Institute of Technology.
    Predictive value of telenursing complaints in influenza surveillance: a prospective cohort study in Sweden2013Conference paper (Other academic)
  • 89.
    Tjomsland, Vegard
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Studies of the tumor microenvironment: Local and systemic effects exerted by the cross-talk between tumor and stroma cells in pancreatic cancer2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Pancreatic cancer is one of the most lethal cancers and despite all research efforts the last 50 years, there are still no effective therapy for this terrible disease. Until quite recently most research in the field of pancreatic duct adenocarcinoma (PDAC) was focused on the tumor cells and mechanisms essential for their proliferation and survival. However, the tumor does not only consist of tumor cells, rather a combination of tumor cells and numerous stroma cell types, i.e. the tumor microenvironment. The tumor cells have developed the ability to activate the surrounding cells to produce factors important for the progression of the tumor. Cancer associated fibroblasts (CAFs) are the major stroma component and as much as 70% of the total PDAC tumor mass consists of these cells. In this thesis I have investigated the mechanisms involved in the cross-talk between tumor cells and CAFs and distinguished the local and systemic effects of this communication. Tumor derived IL-1α was identified as an important factor creating the inflammatory profile seen in CAFs. In PDAC patients, IL-1α was detected in 90% of the tumors and high expression was associated with poor clinical outcome. Moreover, the PDAC tumors had elevated expression levels of many inflammatory factors that were induced in CAFs by the tumor derived IL-1α in vitro. Consequently, this high expression of inflammatory factors in CAFs will attract immune cells including tumor associated macrophages (TAMs), dendritic cells (DCs), and CD8+ T cells. This indicates an immune suppressive role of CAFs, protecting the tumor cells by acting as decoy targets for immune cells homing into the tumor. The inflammatory factors produced in the PDAC microenvironment did not only affect the infiltrating immune cells, but had also systemic effects that included decreased levels of blood DCs in PDAC patients. Furthermore, these myeloid and plasmacytoid DCs were partly activated and had a semi mature phenotype and impaired immunostimulatory function. Low levels of blood DCs were direct associated with poor patient prognosis and the same was seen for low expression of ICOSL by the DCs.

    The findings presented in this thesis indicate an essential role for the cross-talk between tumor cells and stroma in the production of tumor  promoting factors. Treatment of PDAC patients with drugs that target the IL-1α signaling pathway could prevent the communication between these cells, thus reduce the amount of inflammatory factors both locally and systemically. Altogether, our findings support the idea that neutralization of the IL-1α signaling molecule could be a promising therapy for pancreatic cancer.

    The findings presented in this thesis indicate an essential role for the cross-talk between tumor cells and stroma in the production of tumor promoting factors. Treatment of PDAC patients with drugs that target the IL-1α signaling pathway could prevent the communication between these cells, thus reduce the amount of inflammatory factors both locally and systemically. Altogether, our findings support the idea that neutralization of the IL-1α signaling molecule could be a promising therapy for pancreatic cancer.

    List of papers
    1. IL-1α Sustains the Inflammation in Human Pancreatic Cancer Microenvironment by Targeting Cancer Associated Fibroblasts
    Open this publication in new window or tab >>IL-1α Sustains the Inflammation in Human Pancreatic Cancer Microenvironment by Targeting Cancer Associated Fibroblasts
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    2010 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) is dynamic with an extensive interaction between the stroma and tumor cells. Our aim for this study was to delineate the cross-talk between PDAC and cancer-associated fibroblasts (CAFs) with focus on the mechanism creating the chronic inflammatory tumor milieu. We assessed the effect cross talk between primary PDAC and CAF cell lines propagated from tumors had on the creation and sustenance of an inflammatory environment and what factors that were involved in establishing the inflammation.

    The coculture of PDAC and CAF cell lines, propagated from tumor tissues, enhanced the levels of inflammatory factors including IL-1α, IL-6, CXCL8, VEGFA, CCL20, and COX-2. The production of these factors correlated with the expression detected in vivo in PDAC tissues. The key producers of nearly all inflammatory factors were the CAFs and not the tumor cells.

    IL-1α was produced by the tumor cell lines, whereas almost all IL-1RI was expressed by CAFs thus corresponding to their in vivo expression profile in PDAC tissues, indicating a role for the IL-1 signaling cascade in a tumor favorable microenvironment. Neutralization of the IL-1α pathway efficiently diminished the cross talk induced production of inflammatory factors, both in stroma and tumor cells. These data suggest that the cross-talk between PDAC cells and the main stroma cell type, i.e. CAFs, is one contributing factor in the formation of the inflammatory tumor environment and we propose that the neutralization of IL-1α pathway might be a potential therapy for this cancer.

    Keywords
    Tumor stroma cross talk; pancreatic cancer; cancer associated fibroblasts; inflammation; IL-1α
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-67750 (URN)
    Available from: 2011-04-26 Created: 2011-04-26 Last updated: 2011-04-26Bibliographically approved
    2. Pancreatic cancer microenvironment has a high degree of inflammation and infiltrating immune cells in its stroma
    Open this publication in new window or tab >>Pancreatic cancer microenvironment has a high degree of inflammation and infiltrating immune cells in its stroma
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    2010 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Tumor microenvironment is composed of tumor cells, fibroblasts, and infiltrating immune cells, and other cellular components, which work together and create an inflammatory environment favoring tumor progression. The present study aimed to characterize the expression and location of immune cells and investigate inflammatory factors that influence pancreatic ductal adenocarcinoma (PDAC).

    Methods: qPCRs and immunohistological stainings were performed for inflammatory factors and immune cells localized in tumor tissues from patients with PDAC (N=30).

    Results: All PDAC tissues had significant increased levels of inflammatory and chemotactic factors such as IL-1α, COX-2, CXCL8, CCL2, and CCL20 as compared to controls. The PDAC stroma, i.e. the fibrosis surrounding the tumor, was the main producer of these factors with the exception of IL-1α, which was expressed by tumor cells and some infiltrating immune cells. The gene expression for immune cell specific markers CD163, CD1c, CD303, and CD8, corresponding to macrophages, myeloid dendritic cells (DCs), plasmacytoid DCs, and cytotoxic T lymphocytes (CTL), respectively, were all significantly increased in PDAC tissues. Immunostaining of the tumor tissue confirmed the elevated levels of infiltrating macrophages, DCs, mature DCs, and cytotoxic T lymphocytes (CTL). The different immune cells were in nearly all cases localized in the fibrotic tissue adjacent to tumor nests. Production of CXCL8 mRNA and protein by the stroma was dependent on the tumor expression of IL-1α. Of importance, we found a correlation in expression of the proinflammatory factor IL-1α and the PDAC patients’ survival time.

    Conclusion: PDAC cells seem to take advantage of IL-1α to create an inflammatory microenvironment with high degree of fibrosis and the ability to both recruit and activate immune cells and the level of inflammation in this environment influenced the clinical outcome for the patients. Therapies targeting the inflammation might be beneficial for the survival of patients with PDAC.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-67754 (URN)
    Available from: 2011-04-26 Created: 2011-04-26 Last updated: 2011-04-26Bibliographically approved
    3. Pancreatic adenocarcinoma exerts systemic effects on the peripheral blood myeloid and plasmacytoid dendritic cells: an indicator of disease severity?
    Open this publication in new window or tab >>Pancreatic adenocarcinoma exerts systemic effects on the peripheral blood myeloid and plasmacytoid dendritic cells: an indicator of disease severity?
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    2010 (English)In: BMC CANCER, ISSN 1471-2407, Vol. 10, no 87Article in journal (Refereed) Published
    Abstract [en]

    Background: Dendritic cells (DCs) isolated from tumor bearing animals or from individuals with solid tumors display functional abnormalities and the DC impairment has emerged as one mechanism for tumor evasion from the control of the immune system. Ductal pancreatic adenocarcinoma (PDAC), the most common pancreatic cancer, is recognized as a very aggressive cancer type with a mortality that almost matches the rate of incidence. Methods: We examined the systemic influence ductal pancreatic adenocarcinoma ( PDAC) exerted on levels of peripheral blood DCs and inflammatory mediators in comparison to the effects exerted by other pancreatic tumors, chronic pancreatitis, and age-matched controls. Results: All groups examined, including PDAC, had decreased levels of myeloid DCs (MDC) and plasmacytoid DCs (PDC) and enhanced apoptosis in these cells as compared to controls. We found elevated levels of PGE2 and CXCL8 in subjects with PDAC, and chronic pancreatitis. Levels of these inflammatory factors were in part restored in PDAC after tumor resection, whereas the levels of DCs were impaired in the majority of these patients similar to 12 weeks after tumor removal. Our results prove that solid pancreatic tumors, including PDAC, systemically affect blood DCs. The impairments do not seem to be tumor-specific, since similar results were obtained in subjects with chronic pancreatitis. Furthermore, we found that PDAC patients with a survival over 2 years had significant higher levels of blood DCs compared to patients with less than one year survival. Conclusions: Our findings points to the involvement of inflammation in the destruction of the blood MDCs and PDCs. Furthermore, the preservation of the blood DCs compartment in PDAC patients seems to benefit their ability to control the disease and survival.

    Place, publisher, year, edition, pages
    BioMed Central, 2010
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-54869 (URN)10.1186/1471-2407-10-87 (DOI)000276299800001 ()
    Note
    Original Publication: Vegard Tjomsland, Per Sandström, Anna Spangeus, Davorka Messmer, Johan Emilsson, Ursula Falkmer, Sture Falkmer, Karl-Eric Magnusson, Kurt Borch and Marie Larsson, Pancreatic adenocarcinoma exerts systemic effects on the peripheral blood myeloid and plasmacytoid dendritic cells: an indicator of disease severity?, 2010, BMC CANCER, (10), 87. http://dx.doi.org/10.1186/1471-2407-10-87 Licensee: BioMed Central http://www.biomedcentral.com/ Available from: 2010-04-16 Created: 2010-04-16 Last updated: 2011-04-26
    4. Semi Mature Blood Dendritic Cells Exist in Patients with Ductal Pancreatic Adenocarcinoma Owing to Inflammatory Factors Released from the Tumor
    Open this publication in new window or tab >>Semi Mature Blood Dendritic Cells Exist in Patients with Ductal Pancreatic Adenocarcinoma Owing to Inflammatory Factors Released from the Tumor
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    2010 (English)In: PLOS ONE, ISSN 1932-6203, Vol. 5, no 10Article in journal (Refereed) Published
    Abstract [en]

    Background: Much evidence exists regarding the fact that blood DCs, both myeloid DCs (MDCs) and plasmacytoid DCs (PDCs), are negatively affected in different types of cancer, with both reduced numbers and impaired functionality. Functional impairment of DCs in patients with pancreatic ductal adenocarcinoma (PDAC), may contribute to the poor clinical outcome. The aim of this study was to examine the effects PDAC had on blood DCs and elucidate the underlying mechanism responsible for the DC impairment. Methodology/Principal Findings: We examined the systemic influence PDAC exerted on blood DCs by ex vivo measuring numerous activation and maturation markers expressed on these cells. Furthermore, the effect patient plasma and the inflammatory factors CXCL8 and PGE(2) had on purified MDCs and PDCs from healthy donors was assessed and compared to the DCs existing in PDAC patients. We found a partial maturation of the blood MDCs and PDCs in PDAC patients with significantly enhanced expression of CD83, CD40, B7H3, PDL-1, CCR6, and CCR7 and decreased expression of ICOSL, and DCIR. These changes lead to impairment in their immunostimulatory function. Furthermore, chronic pancreatitis gave rise to DCs with similar semi-mature phenotype as seen in PDAC. Low expression of ICOSL was associated with poor prognosis. We found that the mechanism underlying this semi-maturation of DCs was inflammatory factors existing in the PDAC patients plasma. Of note, PGE2, which is elevated PDAC patient plasma, was one contributing factor to the changes seen in MDCs and PDCs phenotype. Conclusion/Significance: Our findings point to a role for the systemic inflammation in transforming blood MDCs and PDCs into semi-mature cells in PDAC patients and we show a correlation between maturation status and clinical outcome. Thus, means to preserve a functional blood DC compartment in PDAC patients by diminishing the inflammation could facilitate their ability to control the disease and improve survival.

    Place, publisher, year, edition, pages
    Public Library of Science (PLoS), 2010
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-61177 (URN)10.1371/journal.pone.0013441 (DOI)000283043700026 ()
    Note

    Original Publication: Vegard Tjomsland, Anna Spångeus, Per Sandström, Kurt Borch, Davorka Messmer and Marie Larsson, Semi Mature Blood Dendritic Cells Exist in Patients with Ductal Pancreatic Adenocarcinoma Owing to Inflammatory Factors Released from the Tumor, 2010, PLOS ONE, (5), 10. http://dx.doi.org/10.1371/journal.pone.0013441 Licensee: Public Library of Science (PLoS) http://www.plos.org/

    Available from: 2010-11-08 Created: 2010-11-05 Last updated: 2014-06-04
  • 90.
    Tjomsland, Vegard
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Bojmar, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Bratthall, Charlotte
    Kalmar Hospital, Sweden.
    Messmer, Davorka
    University of Calif San Diego, CA USA.
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    IL-1α Expression in Pancreatic Ductal Adenocarcinoma Affects the Tumor Cell Migration and Is Regulated by the p38MAPK Signaling Pathway2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8Article in journal (Refereed)
    Abstract [en]

    The interplay between the tumor cells and the surrounding stroma creates inflammation, which promotes tumor growth and spread. The inflammation is a hallmark for pancreatic adenocarcinoma (PDAC) and is to high extent driven by IL-1α. IL-1α is expressed and secreted by the tumor cells and exerting its effect on the stroma, i.e. cancer associated fibroblasts (CAF), which in turn produce massive amount of inflammatory and immune regulatory factors. IL-1 induces activation of transcription factors such as nuclear factor-κβ (NF-κβ), but also activator protein 1 (AP-1) via the small G-protein Ras. Dysregulation of Ras pathways are common in cancer as this oncogene is the most frequently mutated in many cancers. In contrast, the signaling events leading up to the expression of IL-1α by tumor cells are not well elucidated. Our aim was to examine the signaling cascade involved in the induction of IL-1α expression in PDAC. We found p38MAPK, activated by the K-Ras signaling pathway, to be involved in the expression of IL-1α by PDAC as blocking this pathway decreased both the gene and protein expression of IL-1α. Blockage of the P38MAPK signaling in PDAC also dampened the ability of the tumor cell to induce inflammation in CAFs. In addition, the IL-1α autocrine signaling regulated the migratory capacity of PDAC cells. Taken together, the blockage of signaling pathways leading to IL-1α expression and/or neutralization of IL-1α in the PDAC microenvironment should be taken into consideration as possible treatment or complement to existing treatment of this cancer.

  • 91.
    Tjomsland, Vegard
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Niklasson, Lina
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Borch, Kurt
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Druid, Henrik
    Department of Oncology-pathology, Karolinska Institutet, Stockholm, Sweden.
    Bratthall, Charlotte
    Division of Oncology, Kalmar hospital, Kalmar, Sweden.
    Messmer, Davorka
    Cancer Center, University of California San Diego, La Jolla, USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Pancreatic cancer microenvironment has a high degree of inflammation and infiltrating immune cells in its stroma2010Manuscript (preprint) (Other academic)
    Abstract [en]

    Tumor microenvironment is composed of tumor cells, fibroblasts, and infiltrating immune cells, and other cellular components, which work together and create an inflammatory environment favoring tumor progression. The present study aimed to characterize the expression and location of immune cells and investigate inflammatory factors that influence pancreatic ductal adenocarcinoma (PDAC).

    Methods: qPCRs and immunohistological stainings were performed for inflammatory factors and immune cells localized in tumor tissues from patients with PDAC (N=30).

    Results: All PDAC tissues had significant increased levels of inflammatory and chemotactic factors such as IL-1α, COX-2, CXCL8, CCL2, and CCL20 as compared to controls. The PDAC stroma, i.e. the fibrosis surrounding the tumor, was the main producer of these factors with the exception of IL-1α, which was expressed by tumor cells and some infiltrating immune cells. The gene expression for immune cell specific markers CD163, CD1c, CD303, and CD8, corresponding to macrophages, myeloid dendritic cells (DCs), plasmacytoid DCs, and cytotoxic T lymphocytes (CTL), respectively, were all significantly increased in PDAC tissues. Immunostaining of the tumor tissue confirmed the elevated levels of infiltrating macrophages, DCs, mature DCs, and cytotoxic T lymphocytes (CTL). The different immune cells were in nearly all cases localized in the fibrotic tissue adjacent to tumor nests. Production of CXCL8 mRNA and protein by the stroma was dependent on the tumor expression of IL-1α. Of importance, we found a correlation in expression of the proinflammatory factor IL-1α and the PDAC patients’ survival time.

    Conclusion: PDAC cells seem to take advantage of IL-1α to create an inflammatory microenvironment with high degree of fibrosis and the ability to both recruit and activate immune cells and the level of inflammation in this environment influenced the clinical outcome for the patients. Therapies targeting the inflammation might be beneficial for the survival of patients with PDAC.

  • 92.
    Tjomsland, Vegard
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Niklasson, Lina
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Borch, Kurt
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Druid, Henrik
    Karolinska Institute.
    Bratthall, Charlotte
    Kalmar Hospital.
    Messmer, Davorka
    University of Calif San Diego.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    The Desmoplastic Stroma Plays an Essential Role in the Accumulation and Modulation of Infiltrated Immune Cells in Pancreatic Adenocarcinoma2011In: Clinical & Developmental Immunology, ISSN 1740-2522, E-ISSN 1740-2530, Vol. 2011, no 212810Article in journal (Refereed)
    Abstract [en]

    Tumor microenvironment is composed of tumor cells, fibroblasts, and infiltrating immune cells, which all work together and create an inflammatory environment favoring tumor progression. The present study aimed to investigate the role of the desmoplastic stroma in pancreatic ductal adenocarcinoma (PDAC) regarding expression of inflammatory factors and infiltration of immune cells and their impact on the clinical outcome. The PDAC tissues examined expressed significantly increased levels of immunomodulatory and chemotactic factors (IL-6, TGF beta, IDO, COX-2, CCL2, and CCL20) and immune cell-specific markers corresponding to macrophages, myeloid, and plasmacytoid dendritic cells (DCs) as compared to controls. Furthermore, short-time survivors had the lowest levels of DC markers. Immunostainings indicated that the different immune cells and inflammatory factors are mainly localized to the desmoplastic stroma. Therapies modulating the inflammatory tumor microenvironment to promote the attraction of DCs and differentiation of monocytes into functional DCs might improve the survival of PDAC patients.

  • 93.
    Tjomsland, Vegard
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Spangeus, Anna
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences.
    Messmer, Davorka
    University of California.
    Emilsson, Johan
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Falkmer, Ursula
    Jonköping Hospital.
    Falkmer, Sture
    Jonköping Hospital.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Borch, Kurt
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Pancreatic adenocarcinoma exerts systemic effects on the peripheral blood myeloid and plasmacytoid dendritic cells: an indicator of disease severity?2010In: BMC CANCER, ISSN 1471-2407, Vol. 10, no 87Article in journal (Refereed)
    Abstract [en]

    Background: Dendritic cells (DCs) isolated from tumor bearing animals or from individuals with solid tumors display functional abnormalities and the DC impairment has emerged as one mechanism for tumor evasion from the control of the immune system. Ductal pancreatic adenocarcinoma (PDAC), the most common pancreatic cancer, is recognized as a very aggressive cancer type with a mortality that almost matches the rate of incidence. Methods: We examined the systemic influence ductal pancreatic adenocarcinoma ( PDAC) exerted on levels of peripheral blood DCs and inflammatory mediators in comparison to the effects exerted by other pancreatic tumors, chronic pancreatitis, and age-matched controls. Results: All groups examined, including PDAC, had decreased levels of myeloid DCs (MDC) and plasmacytoid DCs (PDC) and enhanced apoptosis in these cells as compared to controls. We found elevated levels of PGE2 and CXCL8 in subjects with PDAC, and chronic pancreatitis. Levels of these inflammatory factors were in part restored in PDAC after tumor resection, whereas the levels of DCs were impaired in the majority of these patients similar to 12 weeks after tumor removal. Our results prove that solid pancreatic tumors, including PDAC, systemically affect blood DCs. The impairments do not seem to be tumor-specific, since similar results were obtained in subjects with chronic pancreatitis. Furthermore, we found that PDAC patients with a survival over 2 years had significant higher levels of blood DCs compared to patients with less than one year survival. Conclusions: Our findings points to the involvement of inflammation in the destruction of the blood MDCs and PDCs. Furthermore, the preservation of the blood DCs compartment in PDAC patients seems to benefit their ability to control the disease and survival.

  • 94.
    Tjomsland, Vegard
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Borch, Kurt
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Messmer, Davorka
    University of California San Diego, CA 92093, USA.
    Larsson, Marie
    University of California San Diego, CA 92093, USA.
    Semi Mature Blood Dendritic Cells Exist in Patients with Ductal Pancreatic Adenocarcinoma Owing to Inflammatory Factors Released from the Tumor2010In: PLOS ONE, ISSN 1932-6203, Vol. 5, no 10Article in journal (Refereed)
    Abstract [en]

    Background: Much evidence exists regarding the fact that blood DCs, both myeloid DCs (MDCs) and plasmacytoid DCs (PDCs), are negatively affected in different types of cancer, with both reduced numbers and impaired functionality. Functional impairment of DCs in patients with pancreatic ductal adenocarcinoma (PDAC), may contribute to the poor clinical outcome. The aim of this study was to examine the effects PDAC had on blood DCs and elucidate the underlying mechanism responsible for the DC impairment. Methodology/Principal Findings: We examined the systemic influence PDAC exerted on blood DCs by ex vivo measuring numerous activation and maturation markers expressed on these cells. Furthermore, the effect patient plasma and the inflammatory factors CXCL8 and PGE(2) had on purified MDCs and PDCs from healthy donors was assessed and compared to the DCs existing in PDAC patients. We found a partial maturation of the blood MDCs and PDCs in PDAC patients with significantly enhanced expression of CD83, CD40, B7H3, PDL-1, CCR6, and CCR7 and decreased expression of ICOSL, and DCIR. These changes lead to impairment in their immunostimulatory function. Furthermore, chronic pancreatitis gave rise to DCs with similar semi-mature phenotype as seen in PDAC. Low expression of ICOSL was associated with poor prognosis. We found that the mechanism underlying this semi-maturation of DCs was inflammatory factors existing in the PDAC patients plasma. Of note, PGE2, which is elevated PDAC patient plasma, was one contributing factor to the changes seen in MDCs and PDCs phenotype. Conclusion/Significance: Our findings point to a role for the systemic inflammation in transforming blood MDCs and PDCs into semi-mature cells in PDAC patients and we show a correlation between maturation status and clinical outcome. Thus, means to preserve a functional blood DC compartment in PDAC patients by diminishing the inflammation could facilitate their ability to control the disease and improve survival.

  • 95.
    Tjomsland, Vegard
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Välilä, Johanna
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Borch, Kurt
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Druid, Henrik
    Department of Oncology-pathology, Karolinska Institutet, Stockholm, Sweden.
    Falkmer, Sture
    Department of Clinical Pathology, County Hospital Ryhov, Jönköping, Sweden.
    Falkmer, Ursula
    Department of Oncology, County Hospital Ryhov, Jönköping, Sweden.
    Messmer, Davorka
    Cancer Center, University of California San Diego, La Jolla, USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    IL-1α Sustains the Inflammation in Human Pancreatic Cancer Microenvironment by Targeting Cancer Associated Fibroblasts2010Manuscript (preprint) (Other academic)
    Abstract [en]

    The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) is dynamic with an extensive interaction between the stroma and tumor cells. Our aim for this study was to delineate the cross-talk between PDAC and cancer-associated fibroblasts (CAFs) with focus on the mechanism creating the chronic inflammatory tumor milieu. We assessed the effect cross talk between primary PDAC and CAF cell lines propagated from tumors had on the creation and sustenance of an inflammatory environment and what factors that were involved in establishing the inflammation.

    The coculture of PDAC and CAF cell lines, propagated from tumor tissues, enhanced the levels of inflammatory factors including IL-1α, IL-6, CXCL8, VEGFA, CCL20, and COX-2. The production of these factors correlated with the expression detected in vivo in PDAC tissues. The key producers of nearly all inflammatory factors were the CAFs and not the tumor cells.

    IL-1α was produced by the tumor cell lines, whereas almost all IL-1RI was expressed by CAFs thus corresponding to their in vivo expression profile in PDAC tissues, indicating a role for the IL-1 signaling cascade in a tumor favorable microenvironment. Neutralization of the IL-1α pathway efficiently diminished the cross talk induced production of inflammatory factors, both in stroma and tumor cells. These data suggest that the cross-talk between PDAC cells and the main stroma cell type, i.e. CAFs, is one contributing factor in the formation of the inflammatory tumor environment and we propose that the neutralization of IL-1α pathway might be a potential therapy for this cancer.

  • 96.
    Tjomsland, Vegard
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Välilä, Johanna
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Borch, Kurt
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Druid, Henrik
    Department of Oncology – Pathology, Karolinska Institutet, Stockholm.
    Falkmer, Sture
    Department of Clinical Pathology, County Hospital Ryhov, Jönköping.
    Falkmer, Ursula
    Department of Oncology, Aalborg University Hospital, Aalborg, Denmark.
    Messmer, Davorka
    Moores Cancer Center, University California San Diego, La Jolla, CA, USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Interleukin 1α sustains the expression of inflammatory factors in human pancreatic cancer microenvironment by targeting cancer-associated fibroblasts2011In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 13, no 8, p. 664-675Article in journal (Refereed)
    Abstract [en]

    The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) is dynamic with an extensive interaction between the stroma and tumor cells. The aim for this study was to delineate the cross-talk between PDAC and cancer-associated fibroblasts (CAFs) with focus on the mechanism creating the chronic inflammatory tumor milieu. We assessed the effects of the cross-talk between primary PDAC and CAF cell lines on the creation and sustenance of the inflammatory tumor microenvironment in pancreatic cancer. The coculture of primary PDAC and CAF cell lines enhanced the levels of inflammatory factors including IL-1á, IL-6, CXCL8, VEGFA, CCL20, and COX-2. CAFs were superior to tumor cells regarding the production of most inflammatory factors and tumor cell associated IL-1á was established as the initiator of the enhanced production of inflammatory factors through the binding of IL-1á to the active IL-1 receptor (IL-1R1) expressed predominantly by CAFs. Furthermore, we found a positive correlation between IL-1á and CXCL8 expression levels in PDAC tissues and correlation between IL-1á expression and the clinical outcome of the patients. This confirmed an important role for the IL-1 signaling cascade in the creation and sustenance of a tumor favorable microenvironment. Neutralization of the IL-1á signaling efficiently diminished the cross-talk induced production of inflammatory factors. These data suggest that the cross-talk between PDAC cells and the main stroma cell type, i.e. CAFs, is one essential factor in the formation of the inflammatory tumor environment and we propose that neutralization of the IL-1á signaling might be a potential therapy for this cancer.

  • 97.
    Tjomsland, Veronica
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Complement activation - good or evil in HIV-1 infection?: interaction of free and complement opsonized HIV-1 with monocyte derived dendritic cells and immune cells in the cervical mucosa2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Worldwide, the heterosexual route is the most common mode of sexual transmission of HIV-1 and women are particularly susceptible to this infection. After penetration of the mucosal epithelium HIV-1 interacts with potential target cells, i.e. dendritic cells (DCs) and CD4+ T cells. The complement system, a key component of the innate immune system, is immediately activated by HIV-1 in vivo. However, HIV-1 can resist complement mediated lysis and become coated with complement fragments and this opsonization influences the viral interaction with immune cells. The DCs are the most potent antigen presenting cell. This cell effectively links the innate recognition of viruses to the generation of an adaptive immune response. However, HIV-1 exploits the function of the DCs to facilitate viral spread and infection. HIV-1 interacts with a range of receptors expressed by the DCs including C-type lectins, integrins and complement receptors (CRs). The uptake of virions by DCs leads to their activation and migration to the lymph nodes. At this site DCs present HIV-1 derived antigen on MHC class I and II molecules and trigger an HIV-1 specific T cell response. The interplay between the virus and the DCs is complex and the initial receptor binding may affect antigen uptake, infection, and antigen presentation.

    The fundamental questions of this thesis are the following: How is free and opsonized HIV-1 internalized, processed, and presented on MHC class I and II molecules by DCs and how do free and opsonized HIV-1 particles interact with immune cells in the cervical mucosa?

    Our results indicate that opsonization of HIV-1 plays a critical role in the interaction with immune cells. Complement opsonization of HIV-1 (C-HIV) significantly enhanced the internalization by the DCs compared to free HIV (F-HIV). Both C-HIV and F-HIV interacted with the CD4 receptor, C-type lectins and integrins. In addition, opsonization of HIV-1 favored an MHC class I presentation by DCs compared to F-HIV. However, the endocytic receptors macrophage mannose receptor, β7 integrin, and CR3 guided the antigens to different compartments with distinct properties and efficiencies for degradation and MHC class I and II presentation of viral antigens. MHC class I presentation of F-HIV and C-HIV was dependent of viral fusion in a CD4/coreceptor dependent manner. Moreover, MHC class II presentation of antigens derived from HIV-1 required endocytosis and proteolysis in acidified compartments. HIV-1 infection of cervical mucosa immune cells and tissue was assessed in a cervical tissue explant model. C-HIV significantly enhanced infection of DCs compared to F-HIV, whereas C-HIV decreased the infection of CD4+ T cells. Blocking the viral use of integrins in the cervical tissue explants significantly decreased the HIV-1 infection of both emigrating DCs and CD4+ T cells and the establishment of founder populations in these tissues. This thesis work has brought forward new facts that can be used to facilitate the development of an effective vaccine or microbicide.

    List of papers
    1. Pathways utilized by dendritic cells for binding, uptake, processing and presentation of antigens derived from HIV-1
    Open this publication in new window or tab >>Pathways utilized by dendritic cells for binding, uptake, processing and presentation of antigens derived from HIV-1
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    2007 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 37, no 7, p. 1752-1763Article in journal (Refereed) Published
    Abstract [en]

    The outcome following HIV infection depends on the nature and durability of the HIV-specific T cell response induced initially. The activation of protective T cell responses depends upon dendritic cells (DC), antigen-presenting cells which have the capacity to process and present viral antigens. DC pulsed with aldrithiol-2-inactivated HIV and delivered in vivo were reported to induce immune responses and promote virologic control in chronically HIV-1-infected subjects. To gain an understanding of this phenomenon, we characterized the steps involved in the presentation of antigens derived from aldrithiol-2-treated vs. infectious HIV-1 by DC. Antigen presentation, on both MHC class I and II, was independent of DC-specific ICAM-3-grabbing integrin, DEC-205 and macrophage mannose receptor, C-type lectins expressed by the DC. Inhibitor studies showed that presentation on MHC class I was dependent on viral fusion in a CD4/coreceptor-dependent manner, both at the cell surface and within endosomes, and access to the classical endosomal processing pathway. MHC class II presentation of HIV-associated antigens was dependent on active endocytosis, probably receptor-mediated, and subsequent degradation of virions in acidified endosomes in the DC. Our study brings forth new facts regarding the binding, uptake, and processing of chemically inactivated virions leading to efficient antigen presentation and should aid in the design of more effective HIV vaccines. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

    Keywords
    Antigen pathway, Antigen presentation, Antigen processing, Dendritic cells, HIV
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-49211 (URN)10.1002/eji.200636981 (DOI)
    Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-12Bibliographically approved
    2. Complement Opsonization of HIV-1 Enhances the Uptake by Dendritic Cells and Involves the Endocytic Lectin and Integrin Receptor Families
    Open this publication in new window or tab >>Complement Opsonization of HIV-1 Enhances the Uptake by Dendritic Cells and Involves the Endocytic Lectin and Integrin Receptor Families
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    2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8Article in journal (Refereed) Published
    Abstract [en]

    Interaction with the complement system is an underappreciated aspect of HIV-1 infection; even in primary infection, complement fragments are found on virions with potential to affect the interplay between the virus and dendritic cells (DC). Since opsonization may affect the efficiency of uptake and the type of receptors utilized, we compared the interactions of DC with free HIV-1 (F-HIV) and complement opsonized HIV-1 (C-HIV). We demonstrate that C-HIV significantly enhanced the uptake by immature DC (IDC) and mature DC (MDC) and that the internalization rate was dependent on both opsonization of the virus and DC maturation state. Increased DC uptake of C-HIV was not due to opsonization related increased binding of virus to the surface of DC but rather increased internalization of C-HIV despite utilizing a similar repertoire of receptors as F-HIV. Both F-HIV and C-HIV interacted with C-type lectins, integrins, and CD4 and blocking these receptor families prevented HIV-1 from binding to DC at 4 degrees C. Blocking integrins significantly reduced the binding and uptake of F-HIV and C-HIV implicating the involvement of several integrins such as beta 1-integrin, CR3, LFA-1, and alpha 4 beta 7. Distinctive for C-HIV was usage of beta 1-integrin and for F-HIV, usage of beta 7-integrin, whereas both F-HIV and C-HIV utilized both integrin chains of CR3. We have in this study identified the receptor types used by both F-HIV and C-HIV to bind to DC. Noteworthy, C-HIV was internalized more efficiently by DC than F-HIV, probably via receptor mediated endocytosis, which may entail different intracellular processing of the virus leading to both elevated infection and altered activation of HIV specific immune responses.

    Place, publisher, year, edition, pages
    Public Library of Science, 2011
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-70749 (URN)10.1371/journal.pone.0023542 (DOI)000293953400051 ()
    Note
    |Available from: 2011-09-16 Created: 2011-09-16 Last updated: 2017-12-08
    3. Complement opsonization of HIV-1 results in a different intracellular processing pattern and efficiency leading to an enhanced MHC I presentation by dendritic cells
    Open this publication in new window or tab >>Complement opsonization of HIV-1 results in a different intracellular processing pattern and efficiency leading to an enhanced MHC I presentation by dendritic cells
    Show others...
    2011 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The antigen processing and presentation processes occurring in dendritic cells (DCs) required for induction of HIV-1 specific T cell responses, which are essential for controlling the viral infection in vivo. The initial interactions of DCs with free HIV-1 (FHIV), or complement opsonized HIV-1 (C-HIV) might influence the routing and nature of pathways used for MHC class I and II restricted presentation. We have examined FHIV, C-HIV, and complement and antibody opsonized HIV-1 (C-IgG-HIV) effects on immature DCs (IDCs) and mature DCs (MDCs) antigen proteolysis, MHC class I and II antigen presentation, and the role of endocytic receptors in presentation of antigens derived from HIV-1. We found that opsonized virions promoted MHC class I presentation by both IDCs and MDCs compared to F-HIV. Indicative of that complement opsonization routes more virions towards the MHC class I presentation pathway. We found that blocking macrophage mannose receptor (MMR) rerouted the HIV-1 to a path leading to higher levels of MHC class I and II presentation. Furthermore, the blocking of β7-integrin also gave an enhanced MHC class I and II presentation by both IDCs and MDCs, whereas the block of αMβ2 integrins, i.e. complement receptor 3 (CR3), decreased the MHC class I and II presentation. In addition, we found that IDCs and MDCs proteolytic activities were modulated by the HIV-1 exposure, for example C-HIV induced an increased proteasome activity in IDCs. Taken together, these findings indicated that endocytic receptors, such as MMR, CR3, and β7 integrin, can promote or disfavor antigen presentation by routing HIV-1 into different endosomal compartments with distinct properties and efficiencies for degradation of viral antigens and MHC class I and II presentation and that HIV-1 affects the antigen processing machineries.

    Keywords
    Dendritic cells, complement opsonized HIV-1, antigen presentation
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-72341 (URN)
    Note
    |Available from: 2011-11-25 Created: 2011-11-25 Last updated: 2011-11-25Bibliographically approved
    4. Blocking of integrins significantly inhibits HIV-1 infection of human cervical mucosa immune cells and development of founder populations
    Open this publication in new window or tab >>Blocking of integrins significantly inhibits HIV-1 infection of human cervical mucosa immune cells and development of founder populations
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    2011 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Slightly more than half of the HIV-1 infected individuals in the world are women and almost all acquire the infection through sexual intercourse. The initial interaction between HIV-1 and the host occurs at the mucosa site and the most common mode to access the submucosa is through dendritic cells (DCs). In the cervical mucosa, HIV-1 exist both as free and opsonized virions and this might influence initial infection. We used a cervical tissue explant model and both free and opsonized virions to study HIV-1 transmission and how it can be prevented.

    We found that complement opsonization significantly enhanced HIV-1 infection of DCs compared to free HIV-1, but this increased infection was not seen for CD4+ T cells. Blocking of α4, β7, and β1 integrins demonstrated significant inhibition of infection of both DCs and CD4+ T cells emigrating from mucosa, independent of the use of free or complement opsonized HIV-1. We found a higher impairment of HIV-1 infection in emigrating DCs for complement opsonized virions compared to free virions when the use of αM/β2 and α4 integrins was blocked.

    This study showed that block of integrins decreased the HIV-1 infection of both DCs and CD4+ T cells emigrating from the cervical explant tissues and, remarkably, the establishment of founder populations in these tissues. This indicates that preventing or severely lowering initial infection of the cervical mucosa could avert systemic HIV-1 infection and should be considered for development of microbicides to prevent HIV infection and transmission.

    Keywords
    Dendritic cells, complement opsonized HIV-1, antigen presentation
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-72342 (URN)
    Available from: 2011-11-25 Created: 2011-11-25 Last updated: 2019-06-28Bibliographically approved
  • 98.
    Tjomsland, Veronica
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Ellegård, Rada
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Burgener, Adam
    National Laboratory for HIV Immunology, Public health Agency of Canada, 1015 Arlington Street Winnipeg, Manitoba, Canada.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Lifson, Jeffrey D
    AIDS and Cancer Virus Program, SAIC Frederick, Inc., National Cancer Institute at Frederick, Frederick, Maryland, USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Complement opsonization of HIV-1 results in a different intracellular processing pattern and efficiency leading to an enhanced MHC I presentation by dendritic cells2011Manuscript (preprint) (Other academic)
    Abstract [en]

    The antigen processing and presentation processes occurring in dendritic cells (DCs) required for induction of HIV-1 specific T cell responses, which are essential for controlling the viral infection in vivo. The initial interactions of DCs with free HIV-1 (FHIV), or complement opsonized HIV-1 (C-HIV) might influence the routing and nature of pathways used for MHC class I and II restricted presentation. We have examined FHIV, C-HIV, and complement and antibody opsonized HIV-1 (C-IgG-HIV) effects on immature DCs (IDCs) and mature DCs (MDCs) antigen proteolysis, MHC class I and II antigen presentation, and the role of endocytic receptors in presentation of antigens derived from HIV-1. We found that opsonized virions promoted MHC class I presentation by both IDCs and MDCs compared to F-HIV. Indicative of that complement opsonization routes more virions towards the MHC class I presentation pathway. We found that blocking macrophage mannose receptor (MMR) rerouted the HIV-1 to a path leading to higher levels of MHC class I and II presentation. Furthermore, the blocking of β7-integrin also gave an enhanced MHC class I and II presentation by both IDCs and MDCs, whereas the block of αMβ2 integrins, i.e. complement receptor 3 (CR3), decreased the MHC class I and II presentation. In addition, we found that IDCs and MDCs proteolytic activities were modulated by the HIV-1 exposure, for example C-HIV induced an increased proteasome activity in IDCs. Taken together, these findings indicated that endocytic receptors, such as MMR, CR3, and β7 integrin, can promote or disfavor antigen presentation by routing HIV-1 into different endosomal compartments with distinct properties and efficiencies for degradation of viral antigens and MHC class I and II presentation and that HIV-1 affects the antigen processing machineries.

  • 99.
    Tjomsland, Veronica
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Ellegård, Rada
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Burgener, Adam
    University of Manitoba, Canada.
    Mogk, Kenzie
    University of Manitoba, Canada.
    Fru Che, Karlhans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Westmacott, Garrett
    National Microbiol Lab, Canada.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Lifson, Jeffrey D.
    SAIC Frederick Inc, MD USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Complement opsonization of HIV-1 results in a different intracellular processing pattern and enhanced MHC class I presentation by dendritic cells2013In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 43, no 6, p. 1470-1483Article in journal (Refereed)
    Abstract [en]

    Induction of optimal HIV-1-specific T-cell responses, which can contribute to controlling viral infection in vivo, depends on antigen processing and presentation processes occurring in DCs. Opsonization can influence the routing of antigen processing and pathways used for presentation. We studied antigen proteolysis and the role of endocytic receptors in MHC class I (MHCI) and II (MHCII) presentation of antigens derived from HIV-1 in human monocyte-derived immature DCs (IDCs) and mature DCs, comparing free and complement opsonized HIV-1 particles. Opsonization of virions promoted MHCI presentation by DCs, indicating that complement opsonization routes more virions toward the MHCI presentation pathway. Blockade of macrophage mannose receptor (MMR) and β7-integrin enhanced MHCI and MHCII presentation by IDCs and mature DCs, whereas the block of complement receptor 3 decreased MHCI and MHCII presentation. In addition, we found that IDC and MDC proteolytic activities were modulated by HIV-1 exposure; complement-opsonized HIV-1 induced an increased proteasome activity in IDCs. Taken together, these findings indicate that endocytic receptors such as MMR, complement receptor 3, and β7-integrin can promote or disfavor antigen presentation probably by routing HIV-1 into different endosomal compartments with distinct efficiencies for degradation of viral antigens and MHCI and MHCII presentation, and that HIV-1 affects the antigen-processing machinery.

  • 100.
    Tjomsland, Veronica
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Ellegård, Rada
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology.
    Fru Che, Karlhans
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Lifson, Jeffrey D
    AIDS and Cancer Virus Program, SAIC Frederick, Inc., National Cancer Institute at Frederick, Frederick, Maryland, USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Complement Opsonization of HIV-1 Enhances the Uptake by Dendritic Cells and Involves the Endocytic Lectin and Integrin Receptor Families2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8Article in journal (Refereed)
    Abstract [en]

    Interaction with the complement system is an underappreciated aspect of HIV-1 infection; even in primary infection, complement fragments are found on virions with potential to affect the interplay between the virus and dendritic cells (DC). Since opsonization may affect the efficiency of uptake and the type of receptors utilized, we compared the interactions of DC with free HIV-1 (F-HIV) and complement opsonized HIV-1 (C-HIV). We demonstrate that C-HIV significantly enhanced the uptake by immature DC (IDC) and mature DC (MDC) and that the internalization rate was dependent on both opsonization of the virus and DC maturation state. Increased DC uptake of C-HIV was not due to opsonization related increased binding of virus to the surface of DC but rather increased internalization of C-HIV despite utilizing a similar repertoire of receptors as F-HIV. Both F-HIV and C-HIV interacted with C-type lectins, integrins, and CD4 and blocking these receptor families prevented HIV-1 from binding to DC at 4 degrees C. Blocking integrins significantly reduced the binding and uptake of F-HIV and C-HIV implicating the involvement of several integrins such as beta 1-integrin, CR3, LFA-1, and alpha 4 beta 7. Distinctive for C-HIV was usage of beta 1-integrin and for F-HIV, usage of beta 7-integrin, whereas both F-HIV and C-HIV utilized both integrin chains of CR3. We have in this study identified the receptor types used by both F-HIV and C-HIV to bind to DC. Noteworthy, C-HIV was internalized more efficiently by DC than F-HIV, probably via receptor mediated endocytosis, which may entail different intracellular processing of the virus leading to both elevated infection and altered activation of HIV specific immune responses.

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