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Ellegård, Rada
Publications (10 of 17) Show all publications
Ellegård, R., Khalid, M., Svanberg, C., Holgersson, H., Thoren, Y., Wittgren, M. K., . . . Larsson, M. (2018). Complement-Opsonized HIV-1 Alters Cross Talk Between Dendritic Cells and Natural Killer (NK) Cells to Inhibit NK Killing and to Upregulate PD-1, CXCR3, and CCR4 on T Cells. Frontiers in Immunology, 9, Article ID 899.
Open this publication in new window or tab >>Complement-Opsonized HIV-1 Alters Cross Talk Between Dendritic Cells and Natural Killer (NK) Cells to Inhibit NK Killing and to Upregulate PD-1, CXCR3, and CCR4 on T Cells
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2018 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 899Article in journal (Refereed) Published
Abstract [en]

Dendritic cells (DCs), natural killer (NK) cells, and T cells play critical roles during primary HIV-1 exposure at the mucosa, where the viral particles become coated with complement fragments and mucosa-associated antibodies. The microenvironment together with subsequent interactions between these cells and HIV at the mucosal site of infection will determine the quality of immune response that ensues adaptive activation. Here, we investigated how complement and immunoglobulin opsonization influences the responses triggered in DCs and NK cells, how this affects their cross talk, and what T cell phenotypes are induced to expand following the interaction. Our results showed that DCs exposed to complement-opsonized HIV (C-HIV) were less mature and had a poor ability to trigger IFN-driven NK cell activation. In addition, when the DCs were exposed to C-HIV, the cytotolytic potentials of both NK cells and CD8 T cells were markedly suppressed. The expression of PD-1 as well as co-expression of negative immune checkpoints TIM-3 and LAG-3 on PD-1 positive cells were increased on both CD4 as well as CD8 T cells upon interaction with and priming by NK-DC cross talk cultures exposed to C-HIV. In addition, stimulation by NK-DC cross talk cultures exposed to C-HIV led to the upregulation of CD38, CXCR3, and CCR4 on T cells. Together, the immune modulation induced during the presence of complement on viral surfaces is likely to favor HIV establishment, dissemination, and viral pathogenesis.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2018
Keywords
dendritic cells; natural killer cells; complement; HIV; cross talk; checkpoint inhibitors; CXCR3; CCR4
National Category
Immunology
Identifiers
urn:nbn:se:liu:diva-147922 (URN)10.3389/fimmu.2018.00899 (DOI)000431174300002 ()29760706 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Physicians against AIDS Research Foundation; VINNMER for Vinnova; Linkoping University Hospital Research Fund; ALF Grants Region Ostergotland; FORSS; CERiA, University of Malaya [UM.C.625/1/HIR/139]

Available from: 2018-05-23 Created: 2018-05-23 Last updated: 2019-05-21
Ellegård, R. (2018). Effects of Complement Opsonization of HIV on Dendritic Cells: and Implications for the Immune Response. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Effects of Complement Opsonization of HIV on Dendritic Cells: and Implications for the Immune Response
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Dendritic cells are key players during HIV pathogenesis, and shape both the immediate immune response at the site of infection as well as directing the adaptive immune response against the virus. HIV has developed a plethora of immune evasion mechanisms that hijack dendritic cell functions, suppressing their ability to mount an accurate immune response and exploiting them for efficient viral transfer to target T cells.

To achieve successful replication within dendritic cells without triggering danger signaling, HIV accomplishes a delicate balance where only a low level of transcription can be sustained without triggering antiviral responses that would harm the virus. Here, we describe how the presence of HSV2 coinfection, which is very common in geographic areas with a high HIV prevalence and almost triples the risk of HIV acquisition, alters dendritic cell state to support much higher levels of HIV infection. We found this effect to be mediated by the STING pathway, which is involved in the sensing of DNA in the cell cytosol. STING activation led to an upregulation of factors such as IRF3 and NFkB that can be used for HIV transcription and a degradation of factors that restrict HIV replication.

In addition, we describe how HIV exploits the human complement system, a group of proteins that usually help the human body to identify dangerous pathogens while avoiding reaction towards self. HIV can coat itself, i.e. become opsonized, in complement fragments that are typically only present on the body’s own cells, allowing it to activate signaling pathways that are associated with tolerance. Dendritic cells that come into contact with complement opsonized HIV do not mount danger responses, despite the fact that HIV-derived single stranded RNA triggers the pathogen recognition receptor TLR8. The suppression of danger responses is mediated by activation of complement receptor 3, and leads to an increased infection of the dendritic cell and affects its interactions with other immune cells. There is a lack of recruitment of NK cells to the site of infection, and an inhibition of NK cell killing, which plays an important role in the destruction of HIV-infected cells in vivo. T cells primed by dendritic cells exposed to complement opsonized HIV have a lower ability to develop towards effector phenotype, and have an increased expression of the markers PD1, TIM3 and LAG3 which are associated with T cell dysfunction and exhaustion. In addition, T cells primed by these dendritic cells in the presence of NK cells upregulate markers CD38, CXCR3 and CCR4, which have been linked to an increased susceptibility to HIV infection.

In summary, we add to the current knowledge on HIV immune evasion mechanisms that allow the virus to establish infection, as well as describing mechanisms that govern whether dendritic cells mount danger signaling and an immune response or not.  

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. p. 65
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1640
Keywords
HIV, dendritic cells, complement, innate immune response, TLR signaling, T cell activation, NK cells, inflammation, antiviral response, immune evasion
National Category
Immunology
Identifiers
urn:nbn:se:liu:diva-151665 (URN)10.3384/diss.diva-151665 (DOI)9789176852217 (ISBN)
Public defence
2018-10-26, Berzeliussalen, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2018-09-28 Created: 2018-09-28 Last updated: 2019-09-30Bibliographically approved
Devito, C., Ellegård, R., Falkeborn, T., Svensson, L., Ohlin, M., Larsson, M., . . . Hinkula, J. (2018). Human IgM monoclonal antibodies block HIV-transmission to immune cells in cervico-vaginal tissues and across polarized epithelial cells in vitro. Scientific Reports, 8, Article ID 10180.
Open this publication in new window or tab >>Human IgM monoclonal antibodies block HIV-transmission to immune cells in cervico-vaginal tissues and across polarized epithelial cells in vitro
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 10180Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:liu:diva-150271 (URN)10.1038/s41598-018-28242-y (DOI)000437413200036 ()29977063 (PubMedID)
Note

Funding Agencies|Swedish Medical Research Fund; MIIC support Fund at Linkoping University

Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2019-05-21
Yien Tan, H., Kong Yong, Y., Shankar, E. M., Paukovics, G., Ellegård, R., Larsson, M., . . . Crowe, S. M. (2016). Aberrant Inflammasome Activation Characterizes Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome. Journal of Immunology, 196(10), 4052-4063
Open this publication in new window or tab >>Aberrant Inflammasome Activation Characterizes Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome
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2016 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 196, no 10, p. 4052-4063Article in journal (Refereed) Published
Abstract [en]

Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) complicates combination antiretroviral therapy (cART) in up to 25% of patients with HIV/TB coinfection. Monocytes and IL-18, a signature cytokine of inflammasome activation, are implicated in TB-IRIS pathogenesis. In this study, we investigated inflammasome activation both pre- and post-cART in TB-IRIS patients. HIV/TB patients exhibited higher proportions of monocytes expressing activated caspase-1 (casp1) pre-cART, compared with HIV patients without TB, and patients who developed TB-IRIS exhibited the greatest increase in casp1 expression. CD64(+) monocytes were a marker of increased casp1 expression. Furthermore, IL-1 beta, another marker of inflammasome activation, was also elevated during TB-IRIS. TB-IRIS patients also exhibited greater upregulation of NLRP3 and AIM2 inflammasome mRNA, compared with controls. Analysis of plasma mitochondrial DNA levels showed that TB-IRIS patients experienced greater cell death, especially pre-cART. Plasma NO levels were lower both pre- and post-cART in TB-IRIS patients, providing evidence of inadequate inflammasome regulation. Plasma IL-18 levels pre-cART correlated inversely with NO levels but positively with monocyte casp1 expression and mitochondrial DNA levels, and expression of IL-18R alpha on CD4(+) T cells and NK cells was higher in TB-IRIS patients, providing evidence that IL-18 is a marker of inflammasome activation. We propose that inflammasome activation in monocytes/macrophages of HIV/TB patients increases with ineffective T cell-dependent activation of monocytes/macrophages, priming them for an excessive inflammatory response after cART is commenced, which is greatest in patients with TB-IRIS.

Place, publisher, year, edition, pages
AMER ASSOC IMMUNOLOGISTS, 2016
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-128934 (URN)10.4049/jimmunol.1502203 (DOI)000375831200008 ()27076678 (PubMedID)
Note

Funding Agencies|University of Malaya; Ministry of Higher Education High Impact Research Grant [UM.C/625/1/HIR/MOHE/MED/01]; University of Malaya Research Grants of the Health and Translational Medicine Research Cluster [RP021A-13HTM, RG448-12HTM]; Research Officer Grant Scheme [BR003-2014]; Australian National Health and Medical Research Council; Swedish Research Council [AI52731]; Swedish Physicians against AIDS Research Foundation; Swedish International Development Cooperation Agency; VINNMER from VINNOVA; Linkoping University Hospital research fund; Governmental Funding of Clinical Research within National Health Service; Swedish Society of Medicine; Victorian Operational Infrastructure Support Program

Available from: 2016-06-09 Created: 2016-06-07 Last updated: 2017-11-30
Crisci, E., Ellegård, R., Nyström, S., Rondahl, E., Serrander, L., Bergström, T., . . . Larsson, M. (2016). Complement opsonization promotes HSV-2 infection of human dendritic cells. Journal of Virology, 90(10), 4939-4950
Open this publication in new window or tab >>Complement opsonization promotes HSV-2 infection of human dendritic cells
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2016 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 90, no 10, p. 4939-4950Article in journal (Refereed) Published
Abstract [en]

Herpes virus type 2 (HSV2) is one of the most common sexually transmitted infections globally with a very high prevalence in many countries. During HSV2 infection viral particles become coated with complement proteins and antibodies, both existent in the genital fluids, which could influence the activation of the immune responses. In genital mucosa, the primary target cells for HSV2 infection are epithelial cells, but resident immune cells such as dendritic cells (DCs) are also infected. The DCs are the activators of the ensuing immune responses directed against HSV2, and the aim of this study was to examine the effects opsonization of HSV2, either with complement alone or with complement and antibodies, had on the infection of immature DCs and their ability to mount inflammatory and antiviral responses. Complement opsonization of HSV2 enhanced both the direct infection of immature DCs and their production of new infectious viral particles. The enhanced infection required activation of the complement cascade and functional complement receptor 3. Furthermore, HSV2 infection of DCs required endocytosis of viral particles and their delivery into an acid endosomal compartment. The presence of complement in combination with HSV1 or HSV2 specific antibodies more or less abolished the HSV2 infection of DCs.Our results clearly demonstrate the importance of studying HSV2 infection under conditions that ensue in vivo, i.e. when the virions are covered in complement fragments and complement fragments and antibodies, as this will shape the infection and the subsequent immune response and needs to be further elucidated.

IMPORTANCE: During HSV2 infection viral particles should become coated with complement proteins and antibodies, both existent in the genital fluids, which could influence the activation of the immune responses. The dendritic cells are the activators of the immune responses directed against HSV2, and the aim of this study was to examine the effects of complement alone or complement and antibodies, on the HSV2 infection of dendritic cells and their ability to mount inflammatory and antiviral responses.Our results demonstrate that the presence of antibodies and complement in the genital environment can influence HSV2 infection under in vitro conditions that reflect the in vivo situation. We believe that our findings are highly relevant for the understanding of HSV2 pathogenesis.

Place, publisher, year, edition, pages
American society of microbiology, 2016
Keywords
HSV2 infection, dendritic cells, complement, antibodies
National Category
Infectious Medicine Microbiology in the medical area
Identifiers
urn:nbn:se:liu:diva-126480 (URN)10.1128/JVI.00224-16 (DOI)000375126100009 ()26937039 (PubMedID)
Note

Funding agencies: Swedish Research Council [AI52731]; Swedish Physicians Against AIDS Research Foundation; Swedish International Development Cooperation Agency; SIDA SARC; VINNMER for Vinnova; Linkoping University Hospital Research Fund; Swedish Society of Medicine; Swedis

Available from: 2016-03-29 Created: 2016-03-29 Last updated: 2018-03-23
Saeidi, A., Ellegård, R., Yong, Y. K., Tan, H. Y., Velu, V., Ussher, J. E., . . . Shankar, E. M. (2016). Functional role of mucosal-associated invariant T cells in HIV infection. Journal of Leukocyte Biology, 100(2), 305-314
Open this publication in new window or tab >>Functional role of mucosal-associated invariant T cells in HIV infection
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2016 (English)In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 100, no 2, p. 305-314Article, review/survey (Refereed) Published
Abstract [en]

MAIT cells represent an evolutionarily conserved, MR1-restricted, innate-like cell subset that express high levels of CD161; have a canonical semi-invariant TCR iV alpha 7.2; and may have an important role in mucosal immunity against various bacterial and fungal pathogens. Mature MAIT cells are CD161(hi)PLZF(hi)IL-18R alpha(+)iV alpha 7.2(+)gamma delta-CD3(+)CD8(+) T cells and occur in the peripheral blood, liver, and mucosa of humans. MAIT cells are activated by a metabolic precursor of riboflavin synthesis presented by MR1 and, therefore, respond to many bacteria and some fungi. Despite their broad antibacterial properties, their functional role in persistent viral infections is poorly understood. Although there is an increasing line of evidence portraying the depletion of MAIT cells in HIV disease, the magnitude and the potential mechanisms underlying such depletion remain unclear. Recent studies suggest that MAIT cells are vulnerable to immune exhaustion as a consequence of HIV and hepatitis C virus infections and HIV/tuberculosis coinfections. HIV infection also appears to cause functional depletion of MAIT cells resulting from abnormal expression of T-bet and EOMES, and effective ART is unable to completely salvage functional MAIT cell loss. Depletion and exhaustion of peripheral MAIT cells may affect mucosal immunity and could increase susceptibility to opportunistic infections during HIV infection. Here, we review some of the important mechanisms associated with depletion and functional loss of MAIT cells and also suggest potential immunotherapeutic strategies to restore MAIT cell functions, including the use of IL-7 to restore effector functions in HIV disease.

Place, publisher, year, edition, pages
FEDERATION AMER SOC EXP BIOL, 2016
Keywords
CD8(+) T cells; cytotoxicity; exhaustion; PD-1; TCR iV alpha 7.2
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:liu:diva-130371 (URN)10.1189/jlb.4RU0216-084R (DOI)000379738600006 ()27256572 (PubMedID)
Note

Funding Agencies|University of Malaya; Ministry of Higher Education [UM.C/625/1/HIR/MOHE/MED/01]; University of Malaya [RP021A-13HTM, RG448-12HTM]; Swedish Research Council [AI52731]; Swedish Physicians Against AIDS Research Foundation; Swedish International Development Cooperation Agency; VINNMER from VINNOVA; Linkoping University Hospital; National Health Service; Swedish Society of Medicine; U.S. National Institutes of Health National Institute of Allergy and Infectious Diseases [1U19AI109633-01]; [BR003-2014]

Available from: 2016-08-15 Created: 2016-08-05 Last updated: 2018-01-10
Barathan, M., Gopal, K., Mohamed, R., Ellegård, R., Saeidi, A., Vadivelu, J., . . . Shankar, E. M. (2015). Chronic hepatitis C virus infection triggers spontaneous differential expression of biosignatures associated with T cell exhaustion and apoptosis signaling in peripheral blood mononucleocytes. Apoptosis (London), 20(4), 466-480
Open this publication in new window or tab >>Chronic hepatitis C virus infection triggers spontaneous differential expression of biosignatures associated with T cell exhaustion and apoptosis signaling in peripheral blood mononucleocytes
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2015 (English)In: Apoptosis (London), ISSN 1360-8185, E-ISSN 1573-675X, Vol. 20, no 4, p. 466-480Article in journal (Refereed) Published
Abstract [en]

Persistent hepatitis C virus (HCV) infection appears to trigger the onset of immune exhaustion to potentially assist viral persistence in the host, eventually leading to hepatocellular carcinoma. The role of HCV on the spontaneous expression of markers suggestive of immune exhaustion and spontaneous apoptosis in immune cells of chronic HCV (CHC) disease largely remain elusive. We investigated the peripheral blood mononuclear cells of CHC patients to determine the spontaneous recruitment of cellular reactive oxygen species (cROS), immunoregulatory and exhaustion markers relative to healthy controls. Using a commercial QuantiGenePlex(A (R)) 2.0 assay, we determined the spontaneous expression profile of 80 different pro- and anti-apoptotic genes in persistent HCV disease. Onset of spontaneous apoptosis significantly correlated with the up-regulation of cROS, indoleamine 2,3-dioxygenase (IDO), cyclooxygenase-2/prostaglandin H synthase (COX-2/PGHS), Foxp3, Dtx1, Blimp1, Lag3 and Cd160. Besides, spontaneous differential surface protein expression suggestive of T cell inhibition viz., TRAIL, TIM-3, PD-1 and BTLA on CD4+ and CD8+ T cells, and CTLA-4 on CD4+ T cells was also evident. Increased up-regulation of Tnf, Tp73, Casp14, Tnfrsf11b, Bik and Birc8 was observed, whereas FasLG, Fas, Ripk2, Casp3, Dapk1, Tnfrsf21, and Cflar were moderately up-regulated in HCV-infected subjects. Our observation suggests the spontaneous onset of apoptosis signaling and T cell exhaustion in chronic HCV disease.

Place, publisher, year, edition, pages
Springer Verlag (Germany), 2015
Keywords
Apoptosis; Caspase; Hepatitis C; Spontaneous immune exhaustion; TRAIL
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-116813 (URN)10.1007/s10495-014-1084-y (DOI)000350669500005 ()25577277 (PubMedID)
Note

Funding Agencies|High Impact Research, University of Malaya [UM.C.625/1/HIR/139]; HIRG-MOHE Grant of University of Malaya [A000003-50001]; Swedish Research Council [AI52731]; Swedish Physicians against AIDS Research Foundation; Swedish International Development Cooperation Agency; SIDA SARC; VINNMER for Vinnova; Linkoping University Hospital Research Fund; CALF; Swedish Society of Medicine; University of Malaya Research Grant (UMRG) of the Health and Translational Medicine Research Cluster, University of Malaya [RG448-12HTM]

Available from: 2015-04-07 Created: 2015-04-07 Last updated: 2017-12-04
Ellegård, R., Crisci, E., Andersson, J., Shankar, E. M., Nyström, S., Hinkula, J. & Larsson, M. (2015). Impaired NK Cell Activation and Chemotaxis toward Dendritic Cells Exposed to Complement-Opsonized HIV-1. Journal of Immunology, 195(4), 1698-1704
Open this publication in new window or tab >>Impaired NK Cell Activation and Chemotaxis toward Dendritic Cells Exposed to Complement-Opsonized HIV-1
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2015 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 195, no 4, p. 1698-1704Article in journal (Refereed) Published
Abstract [en]

Mucosa resident dendritic cells (DCs) may represent one of the first immune cells that HIV-1 encounters during sexual transmission. The virions in body fluids can be opsonized with complement factors because of HIV-mediated triggering of the complement cascade, and this appears to influence numerous aspects of the immune defense targeting the virus. One key attribute of host defense is the ability to attract immune cells to the site of infection. In this study, we investigated whether the opsonization of HIV with complement (C-HIV) or a mixture of complement and Abs (CI-HIV) affected the cytokine and chemokine responses generated by DCs, as well as their ability to attract other immune cells. We found that the expression levels of CXCL8, CXCL10, CCL3, and CCL17 were lowered after exposure to either C-HIV or CI-HIV relative to free HIV (F-HIV). DCs exposed to F-HIV induced higher cell migration, consisting mainly of NK cells, compared with opsonized virus, and the chemotaxis of NK cells was dependent on CCL3 and CXCL10. NK cell exposure to supernatants derived from HIV-exposed DCs showed that F-HIV induced phenotypic activation (e.g., increased levels of TIM3, CD69, and CD25) and effector function (e.g., production of IFN gamma and killing of target cells) in NK cells, whereas C-HIV and CI-HIV did not. The impairment of NK cell recruitment by DCs exposed to complement-opsonized HIV and the lack of NK activation may contribute to the failure of innate immune responses to control HIV at the site of initial mucosa infection.

Place, publisher, year, edition, pages
American Association of Immunologists, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-121313 (URN)10.4049/jimmunol.1500618 (DOI)000360013200039 ()26157174 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Physicians against AIDS Research Foundation [AI52731]; Swedish International Development Cooperation Agency/Swedish Agency for Research Cooperation with Developing Countries-Special Assistant; VINNMER for Vinnova; Linkoping University Hospital Research Fund; central regional agreement on medical training and clinical research (CALF) between Ostergotland County Council and Linkoping University; Swedish Society of Medicine; High Impact Research; University of Malaya [UM.C.625/1/HIR/139]

Available from: 2015-09-16 Created: 2015-09-14 Last updated: 2018-09-28
Ellegård, R., Crisci, E., Burgener, A., Sjöwall, C., Birse, K., Westmacott, G., . . . Larsson, M. (2014). Complement Opsonization of HIV-1 Results in Decreased Antiviral and Inflammatory Responses in Immature Dendritic Cells via CR3. Journal of Immunology, 193(9), 4590-4601
Open this publication in new window or tab >>Complement Opsonization of HIV-1 Results in Decreased Antiviral and Inflammatory Responses in Immature Dendritic Cells via CR3
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2014 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 193, no 9, p. 4590-4601Article in journal (Refereed) Published
Abstract [en]

Immature dendritic cells (iDCs) in genital and rectal mucosa may be one of the first cells to come into contact with HIV-1 during sexual transmission of virus. HIV-1 activates the host complement system, which results in opsonization of virus by inactivated complement fragments, for example, iC3b. We investigated antiviral and inflammatory responses induced in human iDCs after exposure to free HIV-1 (F-HIV), complement-opsonized HIV-1 (C-HIV), and complement and Ab-opsonized HIV-1 (CI-HIV). F-HIV gave rise to a significantly higher expression of antiviral factors such as IFN-beta, myxovirus resistance protein A, and IFN-stimulated genes, compared with C-HIV and CI-HIV. Additionally, F-HIV induced inflammatory factors such as IL-1 beta, IL-6, and TNF-alpha, whereas these responses were weakened or absent after C-HIV or CI-HIV exposure. The responses induced by F-HIV were TLR8-dependent with subsequent activation of IFN regulatory factor 1, p38, ERK, PI3K, and NF-kappa B pathways, whereas these responses were not induced by C-HIV, which instead induced activation of IFN regulatory factor 3 and Lyn. This modulation of TLR8 signaling was mediated by complement receptor 3 and led to enhanced infection. The impact that viral hijacking of the complement system has on iDC function could be an important immune evasion mechanism used by HIV-1 to establish infection in the host.

Place, publisher, year, edition, pages
American Association of Immunologists, 2014
National Category
Basic Medicine
Identifiers
urn:nbn:se:liu:diva-112625 (URN)10.4049/jimmunol.1401781 (DOI)000344079500033 ()25252956 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Physicians against AIDS Research Foundation; Swedish International Development Cooperation Agency; VINNMER for Vinnova; Linkoping University Hospital Research Fund Grant C-ALF; Swedish Society of Medicine; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Swedish Society for Medical Research

Available from: 2014-12-08 Created: 2014-12-05 Last updated: 2018-09-28Bibliographically approved
Shankar, E. M., Vignesh, R., Ellegård, R., Barathan, M., Chong, Y. K., Bador, M. K., . . . Larsson, M. (2014). HIV-Mycobacterium tuberculosis co-infection: a `danger-couplemodel of disease pathogenesis. PATHOGENS AND DISEASE, 70(2), 110-118
Open this publication in new window or tab >>HIV-Mycobacterium tuberculosis co-infection: a `danger-couplemodel of disease pathogenesis
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2014 (English)In: PATHOGENS AND DISEASE, ISSN 2049-632X, Vol. 70, no 2, p. 110-118Article, review/survey (Refereed) Published
Abstract [en]

Tuberculosis (TB) and human immunodeficiency virus (HIV) infection interfere and impact the pathogenesis phenomena of each other. Owing to atypical clinical presentations and diagnostic complications, HIV/TB co-infection continues to be a menace for healthcare providers. Although the increased access to highly active antiretroviral therapy (HAART) has led to a reduction in HIV-associated opportunistic infections and mortality, the concurrent management of HIV/TB co-infection remains a challenge owing to adverse effects, complex drug interactions, overlapping toxicities and tuberculosis -associated immune reconstitution inflammatory syndrome. Several hypotheses have been put forward for the exacerbation of tuberculosis by HIV and vice versa supported by immunological studies. Discussion on the mechanisms produced by infectious cofactors with impact on disease pathology could shed light on how to design potential interventions that could decelerate disease progression. With no vaccine for HIV and lack of an effective vaccine for tuberculosis, it is essential to design strategies against HIV–TB co-infection.

Place, publisher, year, edition, pages
Wiley / Blackwell Publishing Ltd, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-106099 (URN)10.1111/2049-632X.12108 (DOI)000332771500002 ()
Available from: 2014-04-25 Created: 2014-04-24 Last updated: 2014-04-25
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