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  • 1.
    Ahlen, Gustaf
    et al.
    Karolinska University Hospital Huddinge, Sweden .
    Chen, Antony
    Karolinska University Hospital Huddinge, Sweden .
    Roe, Barbara
    University of Coll Dublin, Ireland .
    Falkeborn, Tina
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Frelin, Lars
    Karolinska University Hospital Huddinge, Sweden .
    Hall, William W
    University of Coll Dublin, Ireland .
    Sallberg, Matti
    Karolinska University Hospital Huddinge, Sweden .
    Soderholm, Jonas
    Karolinska University Hospital Huddinge, Sweden University of Gothenburg, Sweden .
    Limited effect on NS3-NS4A protein cleavage after alanine substitutions within the immunodominant HLA-A2-restricted epitope of the hepatitis C virus genotype 3a non-structural 3/4A protease2012In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 93, p. 1680-1686Article in journal (Refereed)
    Abstract [en]

    It has been well established that immunological escape mutations within the hepatitis C virus genotype (gt) la non-structural (NS) 3/4A protease are partly prevented by a reduction in viral protease fitness. Surprisingly little is known about whether similar mutations affect proteases from other genotypes. In the present study, we assessed both the HLA-A2-restricted CTL response and gt3a NS3/4A protease fitness. Similar to gt1, the 1073-1081 epitope was immunodominant within the gt3a-specific HLA-A2-restricted CTL response, despite sequence similarity of only 56% between the gt1a and gt3a genes. However, unlike the gt1a NS3/4A protease, all residues within the gt3a 1073-1081 epitope could be replaced sequentially by alanine while retaining protease activity, at least in part.

  • 2.
    Chang, Chien-Hsing
    et al.
    Morris Plains, New Jersey, United States of America.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Loo, Meiyu
    Morris Plains, New Jersey, United States of America.
    Falkeborn, Tina
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Li, Rongxiu
    Morris Plains, New Jersey, United States of America.
    Cardillo, Thomas M.
    Morris Plains, New Jersey, United States of America.
    Rossi, Edmund A.
    Morris Plains, New Jersey, United States of America.
    Goldenberg, David M.
    Morris Plains, New Jersey, United States of America.
    Wahren, Britta
    Karolinska Institutet, Stockholm, Sweden.
    A Novel Class of Anti-HIV Agents with Multiple Copies of Enfuvirtide Enhances Inhibition of Viral Replication and Cellular Transmission In Vitro2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e41235-e41235Article in journal (Refereed)
    Abstract [en]

    We constructed novel HIV-1 fusion inhibitors that may overcome the current limitations of enfuvirtide, the first such therapeutic in this class. The three prototypes generated by the Dock-and-Lock (DNL) technology to comprise four copies of enfuvirtide tethered site-specifically to the Fc end of different humanized monoclonal antibodies potently neutralize primary isolates (both R5-tropic and X4-tropic), as well as T-cell-adapted strains of HIV-1 in vitro. All three prototypes show EC50 values in the subnanomolar range, which are 10- to 100-fold lower than enfuvirtide and attainable whether or not the constitutive antibody targets HIV-1. The potential of such conjugates to purge latently infected cells was also demonstrated in a cell-to-cell viral inhibition assay by measuring their efficacy to inhibit the spread of HIV-1LAI from infected human peripheral blood mononuclear cells to Jurkat T cells over a period of 30 days following viral activation with 100 nM SAHA (suberoylanilide hydroxamic acid). The IgG-like half-life was not significantly different from that of the parental antibody, as shown by the mean serum concentration of one prototype in mice at 72 h. These encouraging results provide a rationale to develop further novel anti-HIV agents by coupling additional antibodies of interest with alternative HIV-inhibitors via recombinantly-produced, self-assembling, modules.

  • 3.
    Devito, Claudia
    et al.
    Swedish Inst Infect Dis Control, Sweden; HD Dept Clin Virol, Sweden.
    Ellegård, Rada
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Falkeborn, Tina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Microbiology.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ohlin, Mats
    Lund Univ, Sweden.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Broliden, Kristina
    Karolinska Inst, Sweden.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Human IgM monoclonal antibodies block HIV-transmission to immune cells in cervico-vaginal tissues and across polarized epithelial cells in vitro2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 10180Article in journal (Refereed)
    Abstract [en]

    The importance of natural IgM antibodies in protection against infections is still emerging and these antibodies have a potential role in the maintenance of homeostasis through clearance of apoptotic bodies, complement-dependent mechanisms, inflammation and exclusion of misfolded proteins. Natural IgM act as a first line of defence against unknown hazardous factors and are present in most vertebrates. We investigated the functional capacity of anti-HIV-1 IgM monoclonal antibodies, from a combinatorial Fab library derived from healthy individuals, and evaluated their protective role in inhibiting HIV-1 in vitro when passing across the human mucosal epithelial barrier. Primary HIV-1 isolates were efficiently transmitted over the tight polarized epithelial cells when added to their apical surface. Efficient inhibition of HIV-1 transmission was achieved when anti-HIV-1 IgM monoclonal antibodies were added to the basolateral side of the cells. Two of these human IgM MoAbs had the ability to neutralize HIV and reduced infection of dendritic cells in primary cervico-vaginal tissue biopsies in vitro. This indicates a potential role of natural IgM antibodies in the reduction of HIV-1 transmission in mucosal tissues and improve our understanding of how natural IgM antibodies against a neutralizing epitope could interfere with viral transmission.

  • 4.
    Falkeborn, Tina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Nasal vaccination using novel mucosal adjuvants: with main focus on influenza A virus2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Influenza viruses have sporadically caused pandemics during the last century, with the most severe occurring in 1918 when the “Spanish flu”, an A/H1N1 influenza virus, passed around the globe killing about 20-100 million people. Today 250 000-500 000 deaths occur annually due to influenza virus or secondary infection after influenza, e.g. pneumonia. Influenza viruses cause severe infections in susceptible age groups like children and elderly and in individuals with impaired immune response due to other medical conditions. The best way to prevent an influenza epidemic is by vaccination. Since the 1950´s we have vaccines against seasonal flu, but vaccine efficacy is not 100 % and there is a need to develop better and more effective vaccines, especially for the risk groups. Since the virus enters the host through the nasal cavity, nasal vaccination is a good approach. By stimulating a mucosal immune response already in the nasal cavity, the goal with nasal vaccination is to stop the virus before it enters the host. Nasal vaccination also reduces the risk of transmission of blood-borne diseases, and is less painful and easier to administer, compared to injectable vaccines.

    In order to be able to use less immunogenic antigens, like split and subunit antigens, as nasal vaccine components, an adjuvant is needed to enhance the immune response. At the moment there is no licensed mucosal adjuvant for human use. Several studies are ongoing, but it is a complicated and long way to reach the market. In this thesis nasal vaccination with influenza antigen together with the mucosal adjuvant Endocine™ and other mucosal adjuvants has been evaluated. The Endocine™ adjuvant has been shown to be safe and well tolerated in clinical trials. Depending on the pathogen of interest, different approaches are necessary. For HIV, DNA-vaccination has been evaluated together with a plasmid encoding Salmonella typhimurium flagellin C and the mucosal adjuvant N3. The results found in paper I-IV show that by adding adjuvant to the antigen enhances the protective immune response towards the antigen. Enhanced systemic, mucosal and cell-mediated immunity were observed. Hopefully in the future these adjuvants evaluated in this thesis, will be used in vaccines for humans.

    List of papers
    1. Endocine™, N3OA and N3OASq; Three Mucosal Adjuvants That Enhance the Immune Response to Nasal Influenza Vaccination
    Open this publication in new window or tab >>Endocine™, N3OA and N3OASq; Three Mucosal Adjuvants That Enhance the Immune Response to Nasal Influenza Vaccination
    Show others...
    2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8Article in journal (Refereed) Published
    Abstract [en]

    Annual outbreaks of seasonal influenza are controlled or prevented through vaccination in many countries. The seasonal vaccines used are either inactivated, currently administered parenterally, or live-attenuated given intranasally. In this study three mucosal adjuvants were examined for the influence on the humoral (mucosal and systemic) and cellular influenza A-specific immune responses induced by a nasally administered vaccine. We investigated in detail how the anionic Endocine™ and the cationic adjuvants N3OA and N3OASq mixed with a split inactivated influenza vaccine induced influenza A-specific immune responses as compared to the vaccine alone after intranasal immunization. The study showed that nasal administration of a split virus vaccine together with Endocine™ or N3OA induced significantly higher humoral and cell-mediated immune responses than the non-adjuvanted vaccine. N3OASq only significantly increased the cell-mediated immune response. Furthermore, nasal administration of the influenza vaccine in combination with any of the adjuvants; Endocine™, N3OA or N3OASq, significantly enhanced the mucosal immunity against influenza HA protein. Thus the addition of these mucosal adjuvants leads to enhanced immunity in the most relevant tissues, the upper respiratory tract and the systemic circulation. Nasal influenza vaccination with an inactivated split vaccine can therefore provide an important mucosal immune response, which is often low or absent after traditional parenteral vaccination.

    Place, publisher, year, edition, pages
    Public Library of Science, 2013
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-97667 (URN)10.1371/journal.pone.0070527 (DOI)000323124000019 ()
    Note

    Funding Agencies|Eurocine Vaccines||Vinnova Research funds||Halsofonden||

    Available from: 2013-09-19 Created: 2013-09-19 Last updated: 2017-12-06
    2. DNA-Encoded Flagellin Activates Toll-Like Receptor 5 (TLR5), Nod-like Receptor Family CARD Domain-Containing Protein 4 (NRLC4), and Acts as an Epidermal, Systemic, and Mucosal-Adjuvant
    Open this publication in new window or tab >>DNA-Encoded Flagellin Activates Toll-Like Receptor 5 (TLR5), Nod-like Receptor Family CARD Domain-Containing Protein 4 (NRLC4), and Acts as an Epidermal, Systemic, and Mucosal-Adjuvant
    Show others...
    2013 (English)In: Vaccines, ISSN 2076-393X, Vol. 1, no 4, p. 415-443Article in journal (Refereed) Published
    Abstract [en]

    Eliciting effective immune responses using non-living/replicating DNA vaccines is a significant challenge. We have previously shown that ballistic dermal plasmid DNA-encoded flagellin (FliC) promotes humoral as well as cellular immunity to co-delivered antigens. Here, we observe that a plasmid encoding secreted FliC (pFliC(-gly)) produces flagellin capable of activating two innate immune receptors known to detect flagellin; Toll-like Receptor 5 (TLR5) and Nod-like Receptor family CARD domain-containing protein 4 (NRLC4). To test the ability of pFliC(-gly) to act as an adjuvant we immunized mice with plasmid encoding secreted FliC (pFliC(-gly)) and plasmid encoding a model antigen (ovalbumin) by three different immunization routes representative of dermal, systemic, and mucosal tissues. By all three routes we observed increases in antigen-specific antibodies in serum as well as MHC Class I-dependent cellular immune responses when pFliC(-gly) adjuvant was added. Additionally, we were able to induce mucosal antibody responses and Class II-dependent cellular immune responses after mucosal vaccination with pFliC(-gly). Humoral immune responses elicited by heterologus prime-boost immunization with a plasmid encoding HIV-1 from gp160 followed by protein boosting could be enhanced by use of pFliC(-gly). We also observed enhancement of cross-clade reactive IgA as well as a broadening of B cell epitope reactivity. These observations indicate that plasmid-encoded secreted flagellin can activate multiple innate immune responses and function as an adjuvant to non-living/replicating DNA immunizations. Moreover, the capacity to elicit mucosal immune responses, in addition to dermal and systemic properties, demonstrates the potential of flagellin to be used with vaccines designed to be delivered by various routes.

    Place, publisher, year, edition, pages
    Basel, Switzerland: MDPI AG, 2013
    Keywords
    adaptive immunity; DNA adjuvant; flagellin; NLRC4; TLR5
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-99352 (URN)10.3390/vaccines1040415 (DOI)
    Available from: 2013-10-16 Created: 2013-10-16 Last updated: 2015-05-19Bibliographically approved
    3. Comparison of the mucosal adjuvant Endocine™ with two well-known adjuvants: cholera toxin and alum
    Open this publication in new window or tab >>Comparison of the mucosal adjuvant Endocine™ with two well-known adjuvants: cholera toxin and alum
    Show others...
    2015 (English)In: Jacobs Journal of Vaccine and Vaccination, ISSN 2381-2664, Vol. 1, no 1, article id 006Article in journal (Refereed) Published
    Abstract [en]

    To enable efficient mucosal vaccination with split or subunit antigens, an adjuvant is often needed. To date, no mucosal adjuvants are approved for human use, however, there are a variety of mucosal adjuvants in development, including the liposome-based adjuvant Endocine™. The aim of this study was to evaluate split influenza antigens together with Endocine™ and in order to assess the potency of Endocine™, the induction of humoral immune responses were compared to those following influenza vaccination with cholera toxin (CT) or aluminum salt (alum). We show that Endocine™ significantly enhances influenza-specific immune responses in intranasally immunized mice compared to nonadjuvanted vaccine. Furthermore, vaccines adjuvanted with Endocine™ evoked comparable serum IgG and virus neutralizing (VN) antibody titers as nasal vaccines adjuvanted with CT. Compared to parenteral vaccination with alum, Endocine™ triggered significantly higher mucosal and serum IgA titers, and similar VN titers. Taken together, these results support further development of Endocine™ as a mucosal adjuvant and as part of a nasal influenza vaccine candidate.

    Place, publisher, year, edition, pages
    Jacobs Publishers, 2015
    Keywords
    Mucosal adjuvant; nasal immunization; vaccine; Endocine; influenza; neutralizing antibodies
    National Category
    Clinical Laboratory Medicine Cell and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-117979 (URN)
    Available from: 2015-05-19 Created: 2015-05-19 Last updated: 2018-01-11Bibliographically approved
    4. The mucosal adjuvant 1 Endocine™ increases immune responses to influenza antigen in aged mice
    Open this publication in new window or tab >>The mucosal adjuvant 1 Endocine™ increases immune responses to influenza antigen in aged mice
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    More effective influenza vaccines for the elderly population is needed. The vaccines used today are less effective in elderly compared to in adults. It is more difficult to stimulate a protective immune response in elderly due to immunosenescence. Elderly people have a decline in both humoral and cell mediated immunity, which make them more susceptible to viral infections. The aim of this study was to evaluate the mucosal adjuvant Endocine™ together with split influenza antigen in different ages of BALB/c mice (15, 20 and 25 months old). The results from this study show that a nasal influenza vaccine  formulated with Endocine™ enhanced both systemic and mucosal immune responses compared to an unadjuvanted vaccine delivered subcutaneously or intra nasal in aged mice. However, in the 25 months old mice only a very modest immune response was detected. Although the influenza-specific immune responses in aged mice were not induced to the same levels as achieved in young mice, the results show that nasal vaccine formulated with Endocine™ could provide benefits for the elderly.

    National Category
    Clinical Laboratory Medicine Cell and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-117980 (URN)
    Available from: 2015-05-19 Created: 2015-05-19 Last updated: 2018-01-11Bibliographically approved
  • 5.
    Falkeborn, Tina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Asahara, Naomi
    Advanced Medical Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Japan.
    Hayashi, Masayuki
    Advanced Medical Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Japan.
    Arai, Masaaki
    Advanced Medical Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Japan.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Maltais, Anna-Karin
    Eurocine Vaccines AB, Karolinska Institutet Science Park, Solna, Sweden.
    Comparison of the mucosal adjuvant Endocine™ with two well-known adjuvants: cholera toxin and alum2015In: Jacobs Journal of Vaccine and Vaccination, ISSN 2381-2664, Vol. 1, no 1, article id 006Article in journal (Refereed)
    Abstract [en]

    To enable efficient mucosal vaccination with split or subunit antigens, an adjuvant is often needed. To date, no mucosal adjuvants are approved for human use, however, there are a variety of mucosal adjuvants in development, including the liposome-based adjuvant Endocine™. The aim of this study was to evaluate split influenza antigens together with Endocine™ and in order to assess the potency of Endocine™, the induction of humoral immune responses were compared to those following influenza vaccination with cholera toxin (CT) or aluminum salt (alum). We show that Endocine™ significantly enhances influenza-specific immune responses in intranasally immunized mice compared to nonadjuvanted vaccine. Furthermore, vaccines adjuvanted with Endocine™ evoked comparable serum IgG and virus neutralizing (VN) antibody titers as nasal vaccines adjuvanted with CT. Compared to parenteral vaccination with alum, Endocine™ triggered significantly higher mucosal and serum IgA titers, and similar VN titers. Taken together, these results support further development of Endocine™ as a mucosal adjuvant and as part of a nasal influenza vaccine candidate.

  • 6.
    Falkeborn, Tina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Brave, Andreas
    Swedish Institute Communicable Disease Control SMI, Sweden.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. 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, Center for Diagnostics, Department of Clinical Microbiology.
    Schroder, Ulf
    Eurocine Vaccines AB, Sweden.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Endocine™, N3OA and N3OASq; Three Mucosal Adjuvants That Enhance the Immune Response to Nasal Influenza Vaccination2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8Article in journal (Refereed)
    Abstract [en]

    Annual outbreaks of seasonal influenza are controlled or prevented through vaccination in many countries. The seasonal vaccines used are either inactivated, currently administered parenterally, or live-attenuated given intranasally. In this study three mucosal adjuvants were examined for the influence on the humoral (mucosal and systemic) and cellular influenza A-specific immune responses induced by a nasally administered vaccine. We investigated in detail how the anionic Endocine™ and the cationic adjuvants N3OA and N3OASq mixed with a split inactivated influenza vaccine induced influenza A-specific immune responses as compared to the vaccine alone after intranasal immunization. The study showed that nasal administration of a split virus vaccine together with Endocine™ or N3OA induced significantly higher humoral and cell-mediated immune responses than the non-adjuvanted vaccine. N3OASq only significantly increased the cell-mediated immune response. Furthermore, nasal administration of the influenza vaccine in combination with any of the adjuvants; Endocine™, N3OA or N3OASq, significantly enhanced the mucosal immunity against influenza HA protein. Thus the addition of these mucosal adjuvants leads to enhanced immunity in the most relevant tissues, the upper respiratory tract and the systemic circulation. Nasal influenza vaccination with an inactivated split vaccine can therefore provide an important mucosal immune response, which is often low or absent after traditional parenteral vaccination.

  • 7.
    Falkeborn, Tina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Lindberg, Alf
    Eurocine Vaccines AB, Karolinska Institutet Science Park, Solna, Sweden.
    Maltais, Anna-Karin
    Eurocine Vaccines AB, Karolinska Institutet Science Park, Solna, Sweden.
    The mucosal adjuvant 1 Endocine™ increases immune responses to influenza antigen in aged miceManuscript (preprint) (Other academic)
    Abstract [en]

    More effective influenza vaccines for the elderly population is needed. The vaccines used today are less effective in elderly compared to in adults. It is more difficult to stimulate a protective immune response in elderly due to immunosenescence. Elderly people have a decline in both humoral and cell mediated immunity, which make them more susceptible to viral infections. The aim of this study was to evaluate the mucosal adjuvant Endocine™ together with split influenza antigen in different ages of BALB/c mice (15, 20 and 25 months old). The results from this study show that a nasal influenza vaccine  formulated with Endocine™ enhanced both systemic and mucosal immune responses compared to an unadjuvanted vaccine delivered subcutaneously or intra nasal in aged mice. However, in the 25 months old mice only a very modest immune response was detected. Although the influenza-specific immune responses in aged mice were not induced to the same levels as achieved in young mice, the results show that nasal vaccine formulated with Endocine™ could provide benefits for the elderly.

  • 8.
    Nyström, Sanna
    et al.
    Center for Infectious Medicine, F59, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm 141 86, Sweden.
    Bråve, Andreas
    Department of Preparedness, Swedish Institute for Infectious Disease Control, Stockholm 171 82, SwedenDepartment of Preparedness, Swedish Institute for Infectious Disease Control, Stockholm 171 82, Sweden.
    Falkeborn, Tina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine.
    Devito, Claudia
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine.
    Rissiek, Björn
    Center for Infectious Medicine, F59, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm 141 86, Sweden / Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany.
    Johansson, Daniel X
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Nobels väg 16, Stockholm 171 77, Sweden.
    Schröder, Ulf
    Latour AB, Stockholm 171 21, Sweden.
    Uematsu, Satoshi
    Division of Innate immune regulation, International Research and Development Center for Mucosal Vaccine, Institute for Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
    Akira, Shizuo
    Department of Host of Defense, Research Institutet for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine.
    Applequist, Steven E
    Center for Infectious Medicine, F59, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm 141 86, Sweden.
    DNA-Encoded Flagellin Activates Toll-Like Receptor 5 (TLR5), Nod-like Receptor Family CARD Domain-Containing Protein 4 (NRLC4), and Acts as an Epidermal, Systemic, and Mucosal-Adjuvant2013In: Vaccines, ISSN 2076-393X, Vol. 1, no 4, p. 415-443Article in journal (Refereed)
    Abstract [en]

    Eliciting effective immune responses using non-living/replicating DNA vaccines is a significant challenge. We have previously shown that ballistic dermal plasmid DNA-encoded flagellin (FliC) promotes humoral as well as cellular immunity to co-delivered antigens. Here, we observe that a plasmid encoding secreted FliC (pFliC(-gly)) produces flagellin capable of activating two innate immune receptors known to detect flagellin; Toll-like Receptor 5 (TLR5) and Nod-like Receptor family CARD domain-containing protein 4 (NRLC4). To test the ability of pFliC(-gly) to act as an adjuvant we immunized mice with plasmid encoding secreted FliC (pFliC(-gly)) and plasmid encoding a model antigen (ovalbumin) by three different immunization routes representative of dermal, systemic, and mucosal tissues. By all three routes we observed increases in antigen-specific antibodies in serum as well as MHC Class I-dependent cellular immune responses when pFliC(-gly) adjuvant was added. Additionally, we were able to induce mucosal antibody responses and Class II-dependent cellular immune responses after mucosal vaccination with pFliC(-gly). Humoral immune responses elicited by heterologus prime-boost immunization with a plasmid encoding HIV-1 from gp160 followed by protein boosting could be enhanced by use of pFliC(-gly). We also observed enhancement of cross-clade reactive IgA as well as a broadening of B cell epitope reactivity. These observations indicate that plasmid-encoded secreted flagellin can activate multiple innate immune responses and function as an adjuvant to non-living/replicating DNA immunizations. Moreover, the capacity to elicit mucosal immune responses, in addition to dermal and systemic properties, demonstrates the potential of flagellin to be used with vaccines designed to be delivered by various routes.

  • 9.
    Sundén, Birgitta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences.
    Falkeborn, Tina
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences.
    Paues, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Forsum, Urban
    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.
    Lindh, Magnus
    University of Gothenburg.
    Ydrenius, Liselotte
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. 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.
    Serrander, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Real-time PCR detection of Human Herpesvirus 1-5 in patients lacking clinical signs of a viral CNS infection2011In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 11, no 220Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Infections of the central nervous system (CNS) with herpes- or enterovirus can be self-limiting and benign, but occasionally result in severe and fatal disease. The polymerase chain reaction (PCR) has revolutionized the diagnostics of viral pathogens, and by multiple displacement amplification (MDA) prior to real-time PCR the sensitivity might be further enhanced. The aim of this study was to investigate if herpes- or enterovirus can be detected in cerebrospinal fluid (CSF) from patients without symptoms.

    METHODS:

    Cerebrospinal fluid (CSF) samples from 373 patients lacking typical symptoms of viral CNS infection were analysed by real-time PCR targeting herpesviruses or enteroviruses with or without prior MDA.

    RESULTS:

    In total, virus was detected in 17 patients (4%). Epstein-Barr virus (EBV) was most commonly detected, in general from patients with other conditions (e.g. infections, cerebral hemorrhage). MDA satisfactorily amplified viral DNA in the absence of human nucleic acids, but showed poor amplification capacity for viral DNA in CSF samples, and did not increase the sensitivity for herpes virus-detection with our methodology.

    CONCLUSIONS:

    Viral pathogens are rarely detected in CSF from patients without signs of CNS infection, supporting the view that real-time PCR is a highly specific method to detect symptomatic CNS-infection caused by these viruses. However, EBV may be subclinically reactivated due to other pathological conditions in the CNS.

  • 10.
    Younis, Shady
    et al.
    Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden // Department of Animal Production, Ain Shams University, Shoubra El-Kheima, 11241 Cairo, Egypt.
    Kamel, Wael
    Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden.
    Falkeborn, Tina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Microbiology.
    Wang, Hao
    Department of Biochemistry and Biophysics, Stockholm University, SE-10691 Stockholm, Sweden.
    Yu, Di
    Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 23 Uppsala, Sweden.
    Daniels, Robert
    Department of Biochemistry and Biophysics, Stockholm University, SE-10691 Stockholm, Sweden.
    Essand, Magnus
    Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 23 Uppsala, Sweden.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
    Akusjärvi, Göran
    Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden.
    Andersson, Leif
    Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden // Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, SE-75007 Uppsala, Sweden // Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77483, USA.
    Multiple nuclear-replicating viruses require the stress-induced protein ZC3H11A for efficient growth2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 6, p. E3808-E3816Article in journal (Refereed)
    Abstract [en]

    The zinc finger CCCH-type containing 11A (ZC3H11A) gene encodes a well-conserved zinc finger protein that may function in mRNA export as it has been shown to associate with the transcription export (TREX) complex in proteomic screens. Here, we report that ZC3H11A is a stress-induced nuclear protein with RNA-binding capacity that localizes to nuclear splicing speckles. During an adenovirus infection, the ZC3H11A protein and splicing factor SRSF2 relocalize to nuclear regions where viral DNA replication and transcription take place. Knockout (KO) of ZC3H11A in HeLa cells demonstrated that several nuclear-replicating viruses are dependent on ZC3H11A for efficient growth (HIV, influenza virus, herpes simplex virus, and adenovirus), whereas cytoplasmic replicating viruses are not (vaccinia virus and Semliki Forest virus). High-throughput sequencing of ZC3H11A–cross-linked RNA showed that ZC3H11A binds to short purine-rich ribonucleotide stretches in cellular and adenoviral transcripts. We show that the RNA-binding property of ZC3H11A is crucial for its function and localization. In ZC3H11A KO cells, the adenovirus fiber mRNA accumulates in the cell nucleus. Our results suggest that ZC3H11A is important for maintaining nuclear export of mRNAs during stress and that several nuclear-replicating viruses take advantage of this mechanism to facilitate their replication.

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