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1
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Greene TT, Jo Y, Chiale C, Macal M, Fang Z, Khatri FS, Codrington AL, Kazane KR, Akbulut E, Swaminathan S, Fujita Y, Fitzgerald-Bocarsly P, Cordes T, Metallo C, Scott DA, Zúñiga EI. Metabolic deficiencies underlie reduced plasmacytoid dendritic cell IFN-I production following viral infection. Nat Commun 2025; 16:1460. [PMID: 39920132 PMCID: PMC11805920 DOI: 10.1038/s41467-025-56603-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 01/23/2025] [Indexed: 02/09/2025] Open
Abstract
Type I Interferons (IFN-I) are central to host protection against viral infections, with plasmacytoid dendritic cells (pDC) being the most significant source, yet pDCs lose their IFN-I production capacity following an initial burst of IFN-I, resulting in susceptibility to secondary infections. The underlying mechanisms of these dynamics are not well understood. Here we find that viral infection reduces the capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically, we identify lactate dehydrogenase B (LDHB) as a positive regulator of pDC IFN-I production in mice and humans; meanwhile, LDHB deficiency is associated with suppressed IFN-I production, pDC metabolic capacity, and viral control following infection. In addition, preservation of LDHB expression is sufficient to partially retain the function of otherwise exhausted pDCs, both in vitro and in vivo. Furthermore, restoring LDHB in vivo in pDCs from infected mice increases IFNAR-dependent, infection-associated pathology. Our work thus identifies a mechanism for balancing immunity and pathology during viral infections, while also providing insight into the highly preserved infection-driven pDC inhibition.
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Affiliation(s)
- Trever T Greene
- Department of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Yeara Jo
- Department of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Carolina Chiale
- Department of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Monica Macal
- Department of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Ziyan Fang
- Department of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Fawziyah S Khatri
- Department of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Alicia L Codrington
- Department of Pathology, Immunology and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Katelynn R Kazane
- Department of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Elizabeth Akbulut
- Department of Pathology, Immunology and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Shobha Swaminathan
- Department of Medicine, Division of Infectious Disease, The State University of New Jersey, Rutgers, New Jersey Medical School, Newark, NJ, USA
| | - Yu Fujita
- Division of Next-Generation Drug Development, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan
| | | | - Thekla Cordes
- Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, Germany
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA
- Molecular and Cell Biology Laboratory, Salk Institute for Biological Sciences, La Jolla, CA, USA
| | - Christian Metallo
- Molecular and Cell Biology Laboratory, Salk Institute for Biological Sciences, La Jolla, CA, USA
| | - David A Scott
- Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Elina I Zúñiga
- Department of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.
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Ahodantin J, Wu J, Funaki M, Flores J, Wang X, Zheng P, Liu Y, Su L. Siglec-H -/- Plasmacytoid Dendritic Cells Protect Against Acute Liver Injury by Suppressing IFN-γ/Th1 Response and Promoting IL-21 + CD4 T Cells. Cell Mol Gastroenterol Hepatol 2024; 18:101367. [PMID: 38849082 PMCID: PMC11296256 DOI: 10.1016/j.jcmgh.2024.101367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/30/2024] [Accepted: 05/31/2024] [Indexed: 06/09/2024]
Abstract
BACKGROUND & AIMS Siglec-H is a receptor specifically expressed in mouse plasmacytoid dendritic cells (pDCs), which functions as a negative regulator of interferon-α production and plays a critical role in pDC maturation to become antigen-presenting cells. The function of pDCs in autoimmune and inflammatory diseases has been reported. However, the effect of Siglec-H expression in pDCs in liver inflammation and diseases remains unclear. METHODS Using the model of concanavalin A-induced acute liver injury (ALI), we investigated the Siglec-H/pDCs axis during ALI in BDCA2 transgenic mice and Siglec-H-/- mice. Anti-BDCA2 antibody, anti-interleukin (IL)-21R antibody, and Stat3 inhibitor were used to specifically deplete pDCs, block IL21 receptor, and inhibit Stat3 signaling, respectively. Splenocytes and purified naive CD4 T cells and bone marrow FLT3L-derived pDCs were cocultured and stimulated with phorbol myristate acetate/ionomycin and CD3/CD28 beads, respectively. RESULTS Data showed that specific depletion of pDCs aggravated concanavalin A-induced ALI. Remarkably, alanine aminotransferase, hyaluronic acid, and proinflammatory cytokines IL6 and tumor necrosis factor-α levels were lower in the blood and liver of Siglec-H knockout mice. This was associated with attenuation of both interferon-γ/Th1 response and Stat1 signaling in the liver of Siglec-H knockout mice while intrahepatic IL21 and Stat3 signaling pathways were upregulated. Blocking IL21R or Stat3 signaling in Siglec-H knockout mice restored concanavalin A-induced ALI. Finally, we observed that the Siglec-H-null pDCs exhibited immature and immunosuppressive phenotypes (CCR9LowCD40Low), resulting in reduction of CD4 T-cell activation and promotion of IL21+CD4 T cells in the liver. CONCLUSIONS During T-cell-mediated ALI, Siglec-H-null pDCs enhance immune tolerance and promote IL21+CD4 T cells in the liver. Targeting Siglec-H/pDC axis may provide a novel approach to modulate liver inflammation and disease.
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Affiliation(s)
- James Ahodantin
- Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Pharmacology, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland.
| | - Jiapeng Wu
- Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Microbiology and Immunology, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Masaya Funaki
- Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Pharmacology, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Jair Flores
- Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Pharmacology, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Xu Wang
- Division of Immunotherapy, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland
| | | | - Yang Liu
- OncoC4, Inc, Rockville, Maryland
| | - Lishan Su
- Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Pharmacology, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Microbiology and Immunology, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland; Division of Immunotherapy, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland.
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3
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Greene TT, Jo Y, Macal M, Fang Z, Khatri FS, Codrington AL, Kazane KR, Chiale C, Akbulut E, Swaminathan S, Fujita Y, Fitzgerald-Bocarsly P, Cordes T, Metallo C, Scott DA, Zuniga EI. Metabolic Deficiencies Underlie Plasmacytoid Dendritic Cell Exhaustion After Viral Infection. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.28.582551. [PMID: 38464328 PMCID: PMC10925345 DOI: 10.1101/2024.02.28.582551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
Type I Interferons (IFN-I) are central to host protection against viral infections 1 . While any cell can produce IFN-I, Plasmacytoid Dendritic Cells (pDCs) make greater quantities and more varieties of these cytokines than any other cell type 2 . However, following an initial burst of IFN- I, pDCs lose their exceptional IFN-I production capacity and become "exhausted", a phenotype that associates with enhanced susceptibility to secondary infections 3-5 . Despite this apparent cost for the host, pDC exhaustion is conserved across multiple species and viral infections, but the underlying mechanisms and the potential evolutionary advantages are not well understood. Here we characterize pDC exhaustion and demonstrate that it is associated with a reduced capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically, we identify lactate dehydrogenase B (LDHB) as a novel positive regulator of pDC IFN-I production in mice and humans, show that LDHB deficiency is associated with suppressed IFN-I production, pDC metabolic capacity, and viral control following a viral infection, and demonstrate that preservation of LDHB expression is sufficient to partially restore exhausted pDC function in vitro and in vivo . Furthermore, restoring LDHB in vivo in exhausted pDCs increased IFNAR dependent infection- associated pathology. Therefore, our work identifies a novel and conserved mechanism for balancing immunity and pathology during viral infections, while also providing insight into the highly preserved but previously unexplained phenomenon of pDC exhaustion.
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Van der Sluis RM, Holm CK, Jakobsen MR. Plasmacytoid dendritic cells during COVID-19: Ally or adversary? Cell Rep 2022; 40:111148. [PMID: 35858624 PMCID: PMC9279298 DOI: 10.1016/j.celrep.2022.111148] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 06/10/2022] [Accepted: 07/07/2022] [Indexed: 12/12/2022] Open
Abstract
Plasmacytoid dendritic cells (pDCs) are specialized cells of the immune system that are thought to be the main cellular source of type I interferon alpha (IFNα) in response to viral infections. IFNs are powerful antivirals, whereas defects in their function or induction lead to impaired resistance to virus infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. IFN production needs to be controlled, because sustained IFN production can also have detrimental effects on disease outcome. As such, pDCs are likely important for acute antiviral protection against SARS-CoV-2 infection but could potentially also contribute to chronic IFN levels. Here, we provide a historical overview of pDC biology and summarize existing literature addressing their involvement and importance during viral infections of the airways. Furthermore, we outline recent reports focused on the potential role of pDCs during SARS-CoV-2 infection, as well as the potential for this cellular subset to impact COVID-19 disease outcome.
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Dos Santos IP, de Assunção MT, Mauch RM, Sandy NS, Nolasco da Silva MT, Bellomo-Brandão MA, Riccetto AGL. Patients with treated autoimmune hepatitis and persistent suppression of plasmacytoid dendritic cells: A different point of view. Int J Immunopathol Pharmacol 2022; 36:20587384211068667. [PMID: 35404689 PMCID: PMC9006358 DOI: 10.1177/20587384211068667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Objectives: Plasmacytoid dendritic cells (pDCs) have been shown to have a role in autoimmune diseases, but their role in Autoimmune Hepatitis (AIH) is not completely clear. In the present study, we assessed the frequency of pDCs in peripheral blood of AIH patients under long-term standard immunosuppressive therapy. Methods: This cross-sectional analysis enrolled 27 AIH patients and 27 healthy controls. We analyzed and compared their proportion of pDCs, CD4+, CD8+, γδ T cells, CD25+ regulatory T (Treg) cells, FoxP3+, Foxp3+CD39+ Treg cells, total B (CD19+) cells, and plasma cells (CD38+) in peripheral blood using flow cytometry immunophenotyping. Results: AIH patients had a lower percentage of pDCs (median frequencies of 0.2% vs. 0.4%; p = .002) and higher expression of CD8 T cells (32.5% vs 28.6%; p = 0.008) in peripheral blood, when compared to healthy controls. We did not find statistically significant differences between the groups regarding the other cell subtypes.Conclusion: Our data suggest a persistent suppression of pDCs in AIH patients, along with increased CD8 T cell activity, years after AIH diagnosis and despite of good clinical response to treatment, thus pointing to a role of pDCs in the AIH pathogenesis.
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Affiliation(s)
- Irene P Dos Santos
- Center for Hematology and Hemotherapy, 28132University of Campinas, Campinas, Brazil
| | - Mayra T de Assunção
- Pediatric Gastroenterology Clinic, Hospital de Clínicas (University of Campinas Teaching Hospital), 28132University of Campinas, Campinas, Brazil
| | - Renan M Mauch
- Center for Investigation in Pediatrics, School of Medical Sciences, 28132University of Campinas, Campinas, Brazil
| | - Natascha Silva Sandy
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, 7979Hospital for Sick Children, Toronto, ON, Canada
| | - Marcos Tadeu Nolasco da Silva
- Center for Investigation in Pediatrics, School of Medical Sciences, 28132University of Campinas, Campinas, Brazil.,Department of Pediatrics, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Maria Angela Bellomo-Brandão
- Pediatric Gastroenterology Clinic, Hospital de Clínicas (University of Campinas Teaching Hospital), 28132University of Campinas, Campinas, Brazil.,Department of Pediatrics, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Adriana Gut Lopes Riccetto
- Center for Investigation in Pediatrics, School of Medical Sciences, 28132University of Campinas, Campinas, Brazil.,Department of Pediatrics, School of Medical Sciences, University of Campinas, Campinas, Brazil
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6
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Greene TT, Zuniga EI. Type I Interferon Induction and Exhaustion during Viral Infection: Plasmacytoid Dendritic Cells and Emerging COVID-19 Findings. Viruses 2021; 13:1839. [PMID: 34578420 PMCID: PMC8472174 DOI: 10.3390/v13091839] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 09/01/2021] [Accepted: 09/01/2021] [Indexed: 01/12/2023] Open
Abstract
Type I Interferons (IFN-I) are a family of potent antiviral cytokines that act through the direct restriction of viral replication and by enhancing antiviral immunity. However, these powerful cytokines are a caged lion, as excessive and sustained IFN-I production can drive immunopathology during infection, and aberrant IFN-I production is a feature of several types of autoimmunity. As specialized producers of IFN-I plasmacytoid (p), dendritic cells (DCs) can secrete superb quantities and a wide breadth of IFN-I isoforms immediately after infection or stimulation, and are the focus of this review. Notably, a few days after viral infection pDCs tune down their capacity for IFN-I production, producing less cytokines in response to both the ongoing infection and unrelated secondary stimulations. This process, hereby referred to as "pDC exhaustion", favors viral persistence and associates with reduced innate responses and increased susceptibility to secondary opportunistic infections. On the other hand, pDC exhaustion may be a compromise to avoid IFN-I driven immunopathology. In this review we reflect on the mechanisms that initially induce IFN-I and subsequently silence their production by pDCs during a viral infection. While these processes have been long studied across numerous viral infection models, the 2019 coronavirus disease (COVID-19) pandemic has brought their discussion back to the fore, and so we also discuss emerging results related to pDC-IFN-I production in the context of COVID-19.
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Affiliation(s)
| | - Elina I. Zuniga
- Division of Biological Sciences, University of California, San Diego, CA 92093, USA;
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7
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Müller C, Hrynkiewicz R, Bębnowska D, Maldonado J, Baratelli M, Köllner B, Niedźwiedzka-Rystwej P. Immunity against Lagovirus europaeus and the Impact of the Immunological Studies on Vaccination. Vaccines (Basel) 2021; 9:vaccines9030255. [PMID: 33805607 PMCID: PMC8002203 DOI: 10.3390/vaccines9030255] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/08/2021] [Accepted: 03/09/2021] [Indexed: 12/14/2022] Open
Abstract
In the early 1980s, a highly contagious viral hemorrhagic fever in rabbits (Oryctolagus cuniculus) emerged, causing a very high rate of mortality in these animals. Since the initial occurrence of the rabbit hemorrhagic disease virus (RHDV), several hundred million rabbits have died after infection. The emergence of genetically-different virus variants (RHDV GI.1 and GI.2) indicated the very high variability of RHDV. Moreover, with these variants, the host range broadened to hare species (Lepus). The circulation of RHDV genotypes displays different virulences and a limited induction of cross-protective immunity. Interestingly, juvenile rabbits (<9 weeks of age) with an immature immune system display a general resistance to RHDV GI.1, and a limited resistance to RHDV GI.2 strains, whereas less than 3% of adult rabbits survive an infection by either RHDV GI.1. or GI.2. Several not-yet fully understood phenomena characterize the RHD. A very low infection dose followed by an extremely rapid viral replication could be simplified to the induction of a disseminated intravascular coagulopathy (DIC), a severe loss of lymphocytes—especially T-cells—and death within 36 to 72 h post infection. On the other hand, in animals surviving the infection or after vaccination, very high titers of RHDV-neutralizing antibodies were induced. Several studies have been conducted in order to deepen the knowledge about the virus’ genetics, epidemiology, RHDV-induced pathology, and the anti-RHDV immune responses of rabbits in order to understand the phenomenon of the juvenile resistance to this virus. Moreover, several approaches have been used to produce efficient vaccines in order to prevent an infection with RHDV. In this review, we discuss the current knowledge about anti-RHDV resistance and immunity, RHDV vaccination, and the further need to establish rationally-based RHDV vaccines.
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Affiliation(s)
- Claudia Müller
- Department of Experimental Animal Facilities and Biorisk Management, Friedrich-Loeffler-Institute, 17493 Greifswald-Insel Riems, Germany;
| | - Rafał Hrynkiewicz
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland; (R.H.); (D.B.)
| | - Dominika Bębnowska
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland; (R.H.); (D.B.)
| | | | | | - Bernd Köllner
- Institute of Immunology, Friedrich-Loeffler-Institute, 17493 Greifswald-Insel Riems, Germany
- Correspondence: (B.K.); (P.N.-R.)
| | - Paulina Niedźwiedzka-Rystwej
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland; (R.H.); (D.B.)
- Correspondence: (B.K.); (P.N.-R.)
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8
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Greene TT, Jo YR, Zuniga EI. Infection and cancer suppress pDC derived IFN-I. Curr Opin Immunol 2020; 66:114-122. [PMID: 32947131 PMCID: PMC8526282 DOI: 10.1016/j.coi.2020.08.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 08/03/2020] [Accepted: 08/04/2020] [Indexed: 12/12/2022]
Abstract
Plasmacytoid dendritic cells (pDCs) are specialized producers of Type I interferon (IFN-I) that promote anti-viral and anti-tumor immunity. However, chronic infections and cancer inhibit pDC-derived IFN-I. While the mechanisms of this inhibition are multifarious they can be classified broadly into two categories: i) reduction or ablation of pDC IFN-I-production capacity (functional exhaustion) and/or ii) decrease in pDC numbers (altered population dynamics). Recent work has identified many processes that contribute to suppression of pDC-derived IFN-I during chronic infections and cancer, including sustained stimulation through Toll Like Receptors (TLRs), inhibitory microenvironments, inhibitory receptor ligation, and reduced development from bone marrow progenitors and apoptosis. Emerging success leveraging pDCs in treatment of disease through TLR activation illustrates the therapeutic potential of targeting pDCs. Deeper understanding of the systems that limit pDC-derived IFN-I has the potential to improve these emerging therapies as well as help devising new approaches that harness the outstanding IFN-I-production capacity of pDCs.
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Affiliation(s)
- Trever T Greene
- University of California San Diego, Department of Biological Sciences, San Diego, United States
| | - Yea-Ra Jo
- University of California San Diego, Department of Biological Sciences, San Diego, United States
| | - Elina I Zuniga
- University of California San Diego, Department of Biological Sciences, San Diego, United States.
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9
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Soto JA, Gálvez NMS, Andrade CA, Pacheco GA, Bohmwald K, Berrios RV, Bueno SM, Kalergis AM. The Role of Dendritic Cells During Infections Caused by Highly Prevalent Viruses. Front Immunol 2020; 11:1513. [PMID: 32765522 PMCID: PMC7378533 DOI: 10.3389/fimmu.2020.01513] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 06/09/2020] [Indexed: 12/12/2022] Open
Abstract
Dendritic cells (DCs) are a type of innate immune cells with major relevance in the establishment of an adaptive response, as they are responsible for the activation of lymphocytes. Since their discovery, several reports of their role during infectious diseases have been performed, highlighting their functions and their mechanisms of action. DCs can be categorized into different subsets, and each of these subsets expresses a wide arrange of receptors and molecules that aid them in the clearance of invading pathogens. Interferon (IFN) is a cytokine -a molecule of protein origin- strongly associated with antiviral immune responses. This cytokine is secreted by different cell types and is fundamental in the modulation of both innate and adaptive immune responses against viral infections. Particularly, DCs are one of the most important immune cells that produce IFN, with type I IFNs (α and β) highlighting as the most important, as they are associated with viral clearance. Type I IFN secretion can be induced via different pathways, activated by various components of the virus, such as surface proteins or genetic material. These molecules can trigger the activation of the IFN pathway trough surface receptors, including IFNAR, TLR4, or some intracellular receptors, such as TLR7, TLR9, and TLR3. Here, we discuss various types of dendritic cells found in humans and mice; their contribution to the activation of the antiviral response triggered by the secretion of IFN, through different routes of the induction for this important antiviral cytokine; and as to how DCs are involved in human infections that are considered highly frequent nowadays.
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Affiliation(s)
- Jorge A Soto
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Instituto Milenio de Inmunología e Inmunoterapia, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Nicolas M S Gálvez
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Instituto Milenio de Inmunología e Inmunoterapia, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Catalina A Andrade
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Instituto Milenio de Inmunología e Inmunoterapia, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Gaspar A Pacheco
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Instituto Milenio de Inmunología e Inmunoterapia, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Karen Bohmwald
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Instituto Milenio de Inmunología e Inmunoterapia, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Roslye V Berrios
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Instituto Milenio de Inmunología e Inmunoterapia, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Susan M Bueno
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Instituto Milenio de Inmunología e Inmunoterapia, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alexis M Kalergis
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Instituto Milenio de Inmunología e Inmunoterapia, Pontificia Universidad Católica de Chile, Santiago, Chile.,Departamento de Endocrinología, Facultad de Medicina, Instituto Milenio de Inmunología e Inmunoterapia, Pontificia Universidad Católica de Chile, Santiago, Chile
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10
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Doyle EH, Rahman A, Aloman C, Klepper AL, El-Shamy A, Eng F, Rocha C, Kim S, Haydel B, Florman SS, Fiel MI, Schiano T, Branch AD. Individual liver plasmacytoid dendritic cells are capable of producing IFNα and multiple additional cytokines during chronic HCV infection. PLoS Pathog 2019; 15:e1007935. [PMID: 31356648 PMCID: PMC6687199 DOI: 10.1371/journal.ppat.1007935] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 08/08/2019] [Accepted: 06/20/2019] [Indexed: 01/17/2023] Open
Abstract
Plasmacytoid dendritic cells (pDCs) are "natural" interferon α (IFNα)-producing cells. Despite their importance to antiviral defense, autoimmunity, and ischemic liver graft injury, because DC subsets are rare and heterogeneous, basic questions about liver pDC function and capacity to make cytokines remain unanswered. Previous investigations failed to consistently detect IFNα mRNA in HCV-infected livers, suggesting that pDCs may be incapable of producing IFNα. We used a combination of molecular, biochemical, cytometric, and high-dimensional techniques to analyze DC frequencies/functions in liver and peripheral blood mononuclear cells (PBMCs) of hepatitis C virus (HCV)-infected patients, to examine correlations between DC function and gene expression of matched whole liver tissue and liver mononuclear cells (LMCs), and to determine if pDCs can produce multiple cytokines. T cells often produce multiple cytokines/chemokines but until recently technical limitations have precluded tests of polyfunctionality in individual pDCs. Mass cytometry (CyTOF) revealed that liver pDCs are the only LMC that produces detectable amounts of IFNα in response TLR-7/8 stimulation. Liver pDCs secreted large quantities of IFNα (~2 million molecules of IFNα/cell/hour) and produced more IFNα than PBMCs after stimulation, p = 0.0001. LMCs secreted >14-fold more IFNα than IFNλ in 4 hours. Liver pDC frequency positively correlated with whole liver expression of "IFNα-response" pathway (R2 = 0.58, p = 0.007) and "monocyte surface" signature (R2 = 0.54, p = 0.01). Mass cytometry revealed that IFNα-producing pDCs were highly polyfunctional; >90% also made 2-4 additional cytokines/chemokines of our test set of 10. Liver BDCA1 DCs, but not BDCA3 DCs, were similarly polyfunctional. pDCs from a healthy liver were also polyfunctional. Our data show that liver pDCs retain the ability to make abundant IFNα during chronic HCV infection and produce many other immune modulators. Polyfunctional liver pDCs are likely to be key drivers of inflammation and immune activation during chronic HCV infection.
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Affiliation(s)
- Erin Heather Doyle
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Adeeb Rahman
- Human Immune Monitoring Core, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Costica Aloman
- Rush University Medical Center, Chicago, Illinois, United States of America
| | - Arielle L. Klepper
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Ahmed El-Shamy
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Francis Eng
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Chiara Rocha
- Recanati Miller Transplantation Institute, The Mount Sinai Hospital, New York, New York, United States of America
| | - Sang Kim
- Department of Anesthesiology, The Mount Sinai Hospital, New York, New York, United States of America
| | - Brandy Haydel
- Recanati Miller Transplantation Institute, The Mount Sinai Hospital, New York, New York, United States of America
| | - Sander S. Florman
- Recanati Miller Transplantation Institute, The Mount Sinai Hospital, New York, New York, United States of America
| | - M. Isabel Fiel
- Department of Pathology, The Mount Sinai Hospital, New York, New York, United States of America
| | - Thomas Schiano
- Recanati Miller Transplantation Institute, The Mount Sinai Hospital, New York, New York, United States of America
| | - Andrea D. Branch
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- * E-mail:
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11
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Chernykh ER, Oleynik EA, Leplina OY, Starostina NM, Ostanin AA. Dendritic cells in the pathogenesis of viral hepatitis C. RUSSIAN JOURNAL OF INFECTION AND IMMUNITY 2019. [DOI: 10.15789/2220-7619-2019-2-239-252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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12
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Koda Y, Nakamoto N, Chu PS, Ugamura A, Mikami Y, Teratani T, Tsujikawa H, Shiba S, Taniki N, Sujino T, Miyamoto K, Suzuki T, Yamaguchi A, Morikawa R, Sato K, Sakamoto M, Yoshimoto T, Kanai T. Plasmacytoid dendritic cells protect against immune-mediated acute liver injury via IL-35. J Clin Invest 2019; 129:3201-3213. [PMID: 31264967 DOI: 10.1172/jci125863] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 05/14/2019] [Indexed: 12/12/2022] Open
Abstract
Acute liver failure (ALF) is a life-threatening condition, and liver transplantation is the only therapeutic option. Although immune dysregulation is central to its pathogenesis, the precise mechanism remains unclear. Here, we show that the number of peripheral and hepatic plasmacytoid DCs (pDCs) decrease during acute liver injury in both humans and mice. Selective depletion of pDCs in Siglechdtr/+ mice exacerbated concanavalin A-induced acute liver injury. In contrast, adoptively transferred BM-derived pDCs preferentially accumulated in the inflamed liver and protected against liver injury. This protective effect was independent of TLR7 and TLR9 signaling, since a similar effect occurred following transfer of MyD88-deficient pDCs. Alternatively, we found an unexpected immunosuppressive role of pDCs in an IL-35-dependent manner. Both Il12a and Ebi3, heterodimeric components of IL-35, were highly expressed in transferred pDCs and CD4+CD25+ Tregs. However, the protective effect of pDC transfer was completely lost in mice depleted of Tregs by anti-CD25 antibody. Moreover, pDCs derived from IL-35-deficient mice had less of a protective effect both in vivo and in vitro even in the presence of Tregs. These results highlight a unique aspect of pDCs in association with Tregs, serving as a guide for immunotherapeutic options in ALF.
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Affiliation(s)
- Yuzo Koda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.,Mitsubishi Tanabe Pharma Corporation, Kanagawa, Japan
| | - Nobuhiro Nakamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Po-Sung Chu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Aya Ugamura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Yohei Mikami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Toshiaki Teratani
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Hanako Tsujikawa
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Shunsuke Shiba
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Nobuhito Taniki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Tomohisa Sujino
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Kentaro Miyamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Takahiro Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Akihiro Yamaguchi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Rei Morikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Katsuaki Sato
- Division of Immunology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Michiie Sakamoto
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Takayuki Yoshimoto
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.,Japan Agency for Medical Research and Development (AMED), Tokyo, Japan
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13
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Chigbu DI, Loonawat R, Sehgal M, Patel D, Jain P. Hepatitis C Virus Infection: Host⁻Virus Interaction and Mechanisms of Viral Persistence. Cells 2019; 8:cells8040376. [PMID: 31027278 PMCID: PMC6523734 DOI: 10.3390/cells8040376] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 03/25/2019] [Accepted: 04/17/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C (HCV) is a major cause of liver disease, in which a third of individuals with chronic HCV infections may develop liver cirrhosis. In a chronic HCV infection, host immune factors along with the actions of HCV proteins that promote viral persistence and dysregulation of the immune system have an impact on immunopathogenesis of HCV-induced hepatitis. The genome of HCV encodes a single polyprotein, which is translated and processed into structural and nonstructural proteins. These HCV proteins are the target of the innate and adaptive immune system of the host. Retinoic acid-inducible gene-I (RIG-I)-like receptors and Toll-like receptors are the main pattern recognition receptors that recognize HCV pathogen-associated molecular patterns. This interaction results in a downstream cascade that generates antiviral cytokines including interferons. The cytolysis of HCV-infected hepatocytes is mediated by perforin and granzyme B secreted by cytotoxic T lymphocyte (CTL) and natural killer (NK) cells, whereas noncytolytic HCV clearance is mediated by interferon gamma (IFN-γ) secreted by CTL and NK cells. A host-HCV interaction determines whether the acute phase of an HCV infection will undergo complete resolution or progress to the development of viral persistence with a consequential progression to chronic HCV infection. Furthermore, these host-HCV interactions could pose a challenge to developing an HCV vaccine. This review will focus on the role of the innate and adaptive immunity in HCV infection, the failure of the immune response to clear an HCV infection, and the factors that promote viral persistence.
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Affiliation(s)
- DeGaulle I Chigbu
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
- Pennsylvania College of Optometry at Salus University, Elkins Park, PA 19027, USA.
| | - Ronak Loonawat
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
| | - Mohit Sehgal
- Immunology, Microenvironment & Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
| | - Dip Patel
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
| | - Pooja Jain
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
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14
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Hepatitis C virus drives increased type I interferon-associated impairments associated with fibrosis severity in antiretroviral treatment-treated HIV-1-hepatitis C virus-coinfected individuals. AIDS 2017; 31:1223-1234. [PMID: 28492391 DOI: 10.1097/qad.0000000000001455] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Viral coinfections might contribute to the increased immune activation and inflammation that persist in antiretroviral treatment (ART)-treated HIV-1 patients. We investigated whether the hepatitis C virus (HCV) coinfection contributes to such alterations by impairing the plasmacytoid dendritic cell (pDC) IFNα/TLR7 pathway in a highly homogeneous group of ART-treated HIV-1-HCV-coinfected patients. METHODS Twenty-nine HIV-1-infected patients with fully suppressive ART were included, 15 of whom being HCV-coinfected with mild-to-moderate fibrosis and matched for their HIV-1 disease, and 13 control healthy donors. Cellular activation, plasma levels of inflammatory cytokines and pDC transcriptome associated with IFNα/TLR7 pathway were characterized. RESULTS Higher plasma levels of type-I interferon (IFN)-associated cytokines [interferon gamma-induced protein 10 (IP-10), MIP-1β, IL-8 and IFN-inducible T-cell alpha chemoattractant) were observed in HIV-1-HCV-coinfected than in HIV-1-monoinfected patients (P = 0.0007, 0.028, 0.028 and 0.035, respectively). The pDCs and T cells displayed a more exhausted (LAG-3+ and CD57+, respectively) phenotype. The pDC IFNα pathway (defined by phosphorylated STAT1 expression) was constitutively activated in all patients, irrespective of HCV coinfection. Expression of interferon-stimulated genes (ISGs) EI2AK2, ISG15, Mx1 and IFI44 was increased in pDCs from HIV-1-HCV-coinfected individuals and was correlated with fibrosis score (Fibroscan, www.echosens.com, Paris, France and aspartate-aminotransferase/platelet-ratio index score, P = 0.026 and 0.019, respectively). Plasma levels of IP-10, STAT1 expression in pDCs and Mx1 mRNA levels in pDCs decreased after interferon-free anti-HCV treatment. CONCLUSION HCV replication appears to drive increases in type-I IFN-associated inflammation and ISGs expression in pDCs, in association with fibrosis severity in ART-treated HIV-1-infected patients with mild-to-moderate fibrosis. Preliminary results indicate reduction of these alterations with earlier interferon-free anti-HCV treatment in those patients.
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15
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Ka MB, Mezouar S, Ben Amara A, Raoult D, Ghigo E, Olive D, Mege JL. Coxiella burnetii Induces Inflammatory Interferon-Like Signature in Plasmacytoid Dendritic Cells: A New Feature of Immune Response in Q Fever. Front Cell Infect Microbiol 2016; 6:70. [PMID: 27446817 PMCID: PMC4921463 DOI: 10.3389/fcimb.2016.00070] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 06/11/2016] [Indexed: 12/24/2022] Open
Abstract
Plasmacytoid dendritic cells (pDCs) play a major role in antiviral immunity via the production of type I interferons (IFNs). There is some evidence that pDCs interact with bacteria but it is not yet clear whether they are protective or contribute to bacterial pathogenicity. We wished to investigate whether Coxiella burnetii, the agent of Q fever, interacts with pDCs. The stimulation of pDCs with C. burnetii increased the expression of activation and migratory markers (CD86 and CCR7) as determined by flow cytometry and modulated gene expression program as revealed by a microarray approach. Indeed, genes encoding for pro-inflammatory cytokines, chemokines, and type I INF were up-regulated. The up-regulation of type I IFN was correlated with an increase in IFN-α release by C. burnetii-stimulated pDCs. We also investigated pDCs in patients with Q fever endocarditis. Using flow cytometry and a specific gating strategy, we found that the number of circulating pDCs was significantly lower in patients with Q fever endocarditis as compared to healthy donors. In addition, the remaining circulating pDCs expressed activation and migratory markers. As a whole, our study identified non-previously reported activation of pDCs by C. burnetii and their modulation during Q fever.
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Affiliation(s)
- Mignane B Ka
- Unité de Recherche sur les Maladies Infectieuses Tropicales et Emergentes, UMR 63, Centre National de la Recherche Scientifique 7278, INSERM U1095, IRD 198, Aix-Marseille UniversitéMarseille, France; INSERM UMR 1068, Centre de Recherche en Cancérologie de MarseilleMarseille, France
| | - Soraya Mezouar
- Unité de Recherche sur les Maladies Infectieuses Tropicales et Emergentes, UMR 63, Centre National de la Recherche Scientifique 7278, INSERM U1095, IRD 198, Aix-Marseille Université Marseille, France
| | - Amira Ben Amara
- Unité de Recherche sur les Maladies Infectieuses Tropicales et Emergentes, UMR 63, Centre National de la Recherche Scientifique 7278, INSERM U1095, IRD 198, Aix-Marseille Université Marseille, France
| | - Didier Raoult
- Unité de Recherche sur les Maladies Infectieuses Tropicales et Emergentes, UMR 63, Centre National de la Recherche Scientifique 7278, INSERM U1095, IRD 198, Aix-Marseille Université Marseille, France
| | - Eric Ghigo
- Unité de Recherche sur les Maladies Infectieuses Tropicales et Emergentes, UMR 63, Centre National de la Recherche Scientifique 7278, INSERM U1095, IRD 198, Aix-Marseille Université Marseille, France
| | - Daniel Olive
- INSERM UMR 1068, Centre de Recherche en Cancérologie de Marseille Marseille, France
| | - Jean-Louis Mege
- Unité de Recherche sur les Maladies Infectieuses Tropicales et Emergentes, UMR 63, Centre National de la Recherche Scientifique 7278, INSERM U1095, IRD 198, Aix-Marseille Université Marseille, France
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16
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Yoshio S, Kanto T. Host-virus interactions in hepatitis B and hepatitis C infection. J Gastroenterol 2016; 51:409-20. [PMID: 26894594 DOI: 10.1007/s00535-016-1183-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Accepted: 02/06/2016] [Indexed: 02/04/2023]
Abstract
Hepatitis B virus (HBV) and hepatitis C virus (HCV) are among the most endemic pathogens worldwide, with more than 500 million people globally currently infected with these viruses. These pathogens can cause acute and chronic hepatitis that progress to liver cirrhosis or hepatocellular carcinoma. Both viruses utilize multifaceted strategies to evade the host surveillance system and fall below the immunological radar. HBV has developed specific strategies to evade recognition by the innate immune system and is acknowledged to be a stealth virus. However, extensive research has revealed that HBV is recognized by dendritic cells (DCs) and natural killer (NK) cells. Indoleamine-2, 3-dioxygenase is an enforcer of sequential immune reactions in acute hepatitis B, and this molecule has been shown to be induced by the interaction of HBV-infected hepatocytes, DCs, and NK cells. The interleukin-28B genotype has been reported to influence HCV eradication either therapeutically or spontaneously, but the biological function of its gene product, a type-III interferon (IFN-λ3), remains to be elucidated. Human BDCA3(+)DCs have also been shown to be a potent producer of IFN-λ3 in HCV infection, suggesting the possibility that BDCA3(+)DCs could play a key role in developing therapeutic HCV vaccine. Here we review the current state of research on immune responses against HBV and HCV infection, with a specific focus on innate immunity. A comprehensive study based on clinical samples is urgently needed to improve our understanding of the immune mechanisms associated with viral control and thus to develop novel immune modulatory therapies to cure chronic HBV and HCV infection.
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Affiliation(s)
- Sachiyo Yoshio
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, 272-8516, Japan
| | - Tatsuya Kanto
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, 272-8516, Japan.
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17
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Ayala-Fontánez N, Soler DC, McCormick TS. Current knowledge on psoriasis and autoimmune diseases. PSORIASIS-TARGETS AND THERAPY 2016; 6:7-32. [PMID: 29387591 PMCID: PMC5683130 DOI: 10.2147/ptt.s64950] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Psoriasis is a prevalent, chronic inflammatory disease of the skin, mediated by crosstalk between epidermal keratinocytes, dermal vascular cells, and immunocytes such as antigen presenting cells (APCs) and T cells. Exclusive cellular “responsibility” for the induction and maintenance of psoriatic plaques has not been clearly defined. Increased proliferation of keratinocytes and endothelial cells in conjunction with APC/T cell/monocyte/macrophage inflammation leads to the distinct epidermal and vascular hyperplasia that is characteristic of lesional psoriatic skin. Despite the identification of numerous susceptibility loci, no single genetic determinant has been identified as responsible for the induction of psoriasis. Thus, numerous other triggers of disease, such as environmental, microbial and complex cellular interactions must also be considered as participants in the development of this multifactorial disease. Recent advances in therapeutics, especially systemic so-called “biologics” have provided new hope for identifying the critical cellular targets that drive psoriasis pathogenesis. Recent recognition of the numerous co-morbidities and other autoimmune disorders associated with psoriasis, including inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus suggest common signaling elements and cellular mediators may direct disease pathogenesis. In this review, we discuss common cellular pathways and participants that mediate psoriasis and other autoimmune disorders that share these cellular signaling pathways.
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Affiliation(s)
- Nilmarie Ayala-Fontánez
- Department of Dermatology, Case Western Reserve University, Cleveland, OH, USA.,The Murdough Family Center for Psoriasis, University Hospitals Case Medical Center, Cleveland, OH, USA
| | - David C Soler
- Department of Dermatology, Case Western Reserve University, Cleveland, OH, USA.,The Murdough Family Center for Psoriasis, University Hospitals Case Medical Center, Cleveland, OH, USA
| | - Thomas S McCormick
- Department of Dermatology, Case Western Reserve University, Cleveland, OH, USA.,The Murdough Family Center for Psoriasis, University Hospitals Case Medical Center, Cleveland, OH, USA
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18
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Apweiler R, Bairoch A, Wu CH, Barker WC, Boeckmann B, Ferro S, Gasteiger E, Huang H, Lopez R, Magrane M, Martin MJ, Natale DA, O'Donovan C, Redaschi N, Yeh LSL. Host-virus interactions in hepatitis B and hepatitis C infection. J Gastroenterol 2016; 32:D115-9. [PMID: 14681372 PMCID: PMC308865 DOI: 10.1093/nar/gkh131] [Citation(s) in RCA: 2357] [Impact Index Per Article: 261.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatitis B virus (HBV) and hepatitis C virus (HCV) are among the most endemic pathogens worldwide, with more than 500 million people globally currently infected with these viruses. These pathogens can cause acute and chronic hepatitis that progress to liver cirrhosis or hepatocellular carcinoma. Both viruses utilize multifaceted strategies to evade the host surveillance system and fall below the immunological radar. HBV has developed specific strategies to evade recognition by the innate immune system and is acknowledged to be a stealth virus. However, extensive research has revealed that HBV is recognized by dendritic cells (DCs) and natural killer (NK) cells. Indoleamine-2, 3-dioxygenase is an enforcer of sequential immune reactions in acute hepatitis B, and this molecule has been shown to be induced by the interaction of HBV-infected hepatocytes, DCs, and NK cells. The interleukin-28B genotype has been reported to influence HCV eradication either therapeutically or spontaneously, but the biological function of its gene product, a type-III interferon (IFN-λ3), remains to be elucidated. Human BDCA3(+)DCs have also been shown to be a potent producer of IFN-λ3 in HCV infection, suggesting the possibility that BDCA3(+)DCs could play a key role in developing therapeutic HCV vaccine. Here we review the current state of research on immune responses against HBV and HCV infection, with a specific focus on innate immunity. A comprehensive study based on clinical samples is urgently needed to improve our understanding of the immune mechanisms associated with viral control and thus to develop novel immune modulatory therapies to cure chronic HBV and HCV infection.
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Affiliation(s)
- Rolf Apweiler
- The EMBL Outstation--European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
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19
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Crosignani A, Riva A, Della Bella S. Analysis of peripheral blood dendritic cells as a non-invasive tool in the follow-up of patients with chronic hepatitis C. World J Gastroenterol 2016; 22:1393-1404. [PMID: 26819508 PMCID: PMC4721974 DOI: 10.3748/wjg.v22.i4.1393] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Revised: 09/11/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) has a high propensity to establish chronic infections. Failure of HCV-infected individuals to activate effective antiviral immune responses is at least in part related to HCV-induced impairment of dendritic cells (DCs) that play a central role in activating T cell responses. Although the impact of HCV on DC phenotype and function is likely to be more prominent in the liver, major HCV-induced alterations are detectable in peripheral blood DCs (pbDCs) that represent the most accessible source of DCs. These alterations include numerical reduction, impaired production of inflammatory cytokines and increased production of immunosuppressive IL10. These changes in DCs are relevant to our understanding the immune mechanisms underlying the propensity of HCV to establish persistent infection. Importantly, the non-invasive accessibility of pbDCs renders the analysis of these cells a convenient procedure that can be serially repeated in patient follow-up. Accordingly, the study of pbDCs in HCV-infected patients during conventional treatment with pegylated interferon and ribavirin indicated that restoration of normal plasmacytoid DC count may represent an additional mechanism contributing to the efficacy of the dual therapy. It also identified the pre-treatment levels of plasmacytoid DCs and IL10 as putative predictors of response to therapy. Treatment of chronic HCV infection is changing, as new generation direct-acting antiviral agents will soon be available for use in interferon-free therapeutic strategies. The phenotypic and functional analysis of pbDCs in this novel therapeutic setting will provide a valuable tool for investigating mechanisms underlying treatment efficacy and for identifying predictors of treatment response.
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20
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Increased proportions of dendritic cells and recovery of IFNγ responses in HIV/HCV co-infected patients receiving ART. Hum Immunol 2015; 77:29-34. [PMID: 26455474 DOI: 10.1016/j.humimm.2015.10.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 07/29/2015] [Accepted: 10/05/2015] [Indexed: 12/24/2022]
Abstract
Dendritic cell (DC) numbers and functions can be affected by HIV and HCV disease, but the effects of antiretroviral therapy (ART) on DC and the implications of these changes are unclear. We examined circulating DC in samples from Indonesian patients beginning ART with advanced HIV disease and documented mild/moderate HCV hepatitis. Frequencies of myeloid and plasmacytoid DC increased after 6 months on ART, but frequencies of DC producing IL-12 or IFNα following stimulation with TLR agonists (CL075, CpG) did not change. IFNγ responses to CL075, HCV and other antigens rose over this period. Hence increased IFNγ responses during ART may be associated with increased DC frequencies rather than changes in their functional capacity.
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21
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Abstract
Cytokines are intercellular mediators involved in viral control and liver damage being induced by infection with hepatitis C virus (HCV). The complex cytokine network operating during initial infection allows a coordinated, effective development of both innate and adaptive immune responses. However, HCV interferes with cytokines at various levels and escapes immune response by inducing a T-helper (Th)2/T cytotoxic 2 cytokine profile. Inability to control infection leads to the recruitment of inflammatory infiltrates into the liver parenchyma by interferon (IFN)-γ-inducible CXC chemokine ligand (CXCL)9, -10, and -11 chemokines, which results in sustained liver damage and eventually in liver cirrhosis. The most important systemic HCV-related extrahepatic diseases-mixed cryoglobulinemia, lymphoproliferative disorders, thyroid autoimmune disorders, and type 2 diabetes-are associated with a complex dysregulation of the cytokine/chemokine network, involving proinflammatory and Th1 chemokines. The therapeutical administration of cytokines such as IFN-α may result in viral clearance during persistent infection and revert this process. Theoretically agents that selectively neutralize CXCL10 could increase patient responsiveness to traditional IFN-based HCV therapy. Several studies have reported IL-28B polymorphisms and circulating CXCL10 may be a prognostic markers for HCV treatment efficacy in HCV genotype 1 infection.
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Affiliation(s)
- Alessandro Antonelli
- Department of Clinical and Experimental Medicine, University of Pisa, Via Savi, 10, 56126, Pisa, Italy,
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22
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Cho CH, Yoon SY, Lee CK, Lim CS, Cho Y. Effect of Interleukin-29 on Interferon-α Secretion by Peripheral Blood Mononuclear Cells. CELL JOURNAL 2015; 16:528-37. [PMID: 25685743 PMCID: PMC4297491 DOI: 10.22074/cellj.2015.497] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Accepted: 04/19/2014] [Indexed: 01/12/2023]
Abstract
Objective The effect of interleukin (IL)-29, a new therapeutic agent similar to type I interferons (IFNs), on IFN-α secretion of human plasmacytoid dendritic cells (pDCs) has
not been studied. Therefore, in this study, we aimed to clarify the effect of IL-29 on IFN-α
secretion of pDCs using human peripheral blood mononuclear cells (PBMCs) in the presence of cytosine-phosphate-guanosinemotif-containing oligodeoxy nucleotides (CpG).
Materials and Methods In this experimental and prospective study, PBMCs were ob-
tained from 11 healthy volunteers and divided into four culture conditions: I. control, II.
CpG treatment, III. IL-29 treatment and IV. CpG plus IL-29 treatment. The amount of IFN-α
secretion was measured from each culture supernatant by flow cytometry using the flowcytomix apparatus (eBioscience, Vienna, Austria). Fractional IFN-α production of the cultured PBMCs was measured by intracellular staining using the cytomics FC 500 system
(Beckman Coulter, Brea, CA, USA) with CXP Software.
Results The mean ± standard deviation (SD) of supernatant IFN-α secretion per pDC/μL was
5.7 ± 9.3 pg/mL/count/µL for condition I, 1071.5 ± 1026.6 pg/mL/count/µL for condition II, 14.1
± 21.1 pg/mL/count/µL for condition III, and 1913.9 ± 1525.9 pg/mL/count/µL for condition IV.
There were statistically significant differences between conditions I and II as well as betweenconditions II and IV. Intracellular IFN-α production was only detectable in the pDC fraction from
one culture; the production amount was similar between the cells treated with CpG and those
treated with CpG plus IL-29. Natural killer (NK) cell production of IFN-α was observed in two out
of three cultures and one culture showed IFN- α production in the monocyte fraction.
Conclusion IL-29 alone did not show any effect on IFN-α secretion of PBMCs. However,
the addition of CpG along with IL-29 enhanced IFN-α secretion of PBMCs. Given that
pDCs are the major secretors of IFN-α in peripheral blood, this result has suggested the
possibility that IL-29 has an enhancing effect in human pDC IFN-α secretion. Although the
supernatant IFN-α secretion was not directly correlated with pDCs’s intracellular IFN-α
production in this study, prolonged incubation of pDC and other PB subsets with CpG
or IL-29 for over 4 hours could be applied in future studies. These studies would help to
elucidate the mechanism of action of IL-29 in human pDCs associated with viral infections.
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Affiliation(s)
- Chi Hyun Cho
- Department of Laboratory Medicine, College of Medicine, Korea University, Seoul, Korea
| | - Soo Young Yoon
- Department of Laboratory Medicine, College of Medicine, Korea University, Seoul, Korea
| | - Chang Kyu Lee
- Department of Laboratory Medicine, College of Medicine, Korea University, Seoul, Korea
| | - Chae Seung Lim
- Department of Laboratory Medicine, College of Medicine, Korea University, Seoul, Korea
| | - Yunjung Cho
- Department of Laboratory Medicine, College of Medicine, Korea University, Seoul, Korea
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Efficient virus assembly, but not infectivity, determines the magnitude of hepatitis C virus-induced interferon alpha responses of plasmacytoid dendritic cells. J Virol 2014; 89:3200-8. [PMID: 25552725 DOI: 10.1128/jvi.03229-14] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
UNLABELLED Worldwide, approximately 160 million people are chronically infected with hepatitis C virus (HCV), seven distinct genotypes of which are discriminated. The hallmarks of HCV are its genetic variability and the divergent courses of hepatitis C progression in patients. We assessed whether intragenotypic HCV variations would differentially trigger host innate immunity. To this end, we stimulated human primary plasmacytoid dendritic cells (pDC) with crude preparations of different cell culture-derived genotype 2a HCV variants. Parental Japanese fulminant hepatitis C virus (JFH1) did not induce interferon alpha (IFN-α), whereas the intragenotypic chimera Jc1 triggered massive IFN-α responses. Purified Jc1 retained full infectivity but no longer induced IFN-α. Coculture of pDC with HCV-infected hepatoma cells retrieved the capacity to induce IFN-α, whereas Jc1-infected cells triggered stronger responses than JFH1-infected cells. Since the infectivity of virus particles did not seem to affect pDC activation, we next tested Jc1 mutants that were arrested at different stages of particle assembly. These experiments revealed that efficient assembly and core protein envelopment were critically needed to trigger IFN-α. Of note, sequences within domain 2 of the core that vitally affect virus assembly also crucially influenced the IFN-α responses of pDC. These data showed that viral determinants shaped host innate IFN-α responses to HCV. IMPORTANCE Although pegylated IFN-α plus ribavirin currently is the standard of care for the treatment of chronic hepatitis C virus infection, not much is known about the relevance of early interferon responses in the pathogenesis of hepatitis C virus infection. Here, we addressed whether intragenotypic variations of hepatitis C virus would account for differential induction of type I interferon responses mounted by primary blood-derived plasmacytoid dendritic cells. Surprisingly, a chimeric genotype 2a virus carrying the nonstructural genes of Japanese fulminant hepatitis C virus (JFH1) induced massive type I interferon responses, whereas the original genotype 2a JFH1 strain did not. Our detailed analyses revealed that, not the virus infectivity, but rather, the efficiency of virus assembly and core protein envelopment critically determined the magnitude of interferon responses. To our knowledge, this is the first example of hepatitis C virus-associated genetic variations that determine the magnitude of innate host responses.
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O’Connor KS, George J, Booth D, Ahlenstiel G. Dendritic cells in hepatitis C virus infection: key players in the IFNL3-genotype response. World J Gastroenterol 2014; 20:17830-8. [PMID: 25548481 PMCID: PMC4273133 DOI: 10.3748/wjg.v20.i47.17830] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Revised: 07/14/2014] [Accepted: 07/24/2014] [Indexed: 02/06/2023] Open
Abstract
Recently, single nucleotide polymorphisms, in the vicinity of the interferon lambda 3 (IFNL3) gene have been identified as the strongest predictor of spontaneous and treatment induced clearance of hepatitis C virus (HCV) infection. Since then, increasing evidence has implicated the innate immune response in mediating the IFNL3 genotype effect. Dendritic cells (DCs) are key to the host immune response in HCV infection and their vital role in the IFNL3 genotype effect is emerging. Reports have identified subclasses of DCs, particularly myeloid DC2s and potentially plasmacytoid DCs as the major producers of IFNL3 in the setting of HCV infection. Given the complexities of dendritic cell biology and the conflicting current available data, this review aims to summarize what is currently known regarding the role of dendritic cells in HCV infection and to place it into context of what is know about lambda interferons and dendritic cells in general.
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Leplina OY, Tyrinova TV, Tikhonova MA, Ostanin AA, Chernykh ER. Interferon alpha induces generation of semi-mature dendritic cells with high pro-inflammatory and cytotoxic potential. Cytokine 2014; 71:1-7. [PMID: 25174880 DOI: 10.1016/j.cyto.2014.07.258] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Accepted: 07/31/2014] [Indexed: 01/04/2023]
Abstract
Dendritic cell-based vaccines are considered as a new and promising immunotherapeutic approach for cancer treatment. However, the choice of optimal protocol of dendritic cell generation in vitro represents the major challenge. Here, we compared phenotype and functional characteristics of human monocyte-derived dendritic cells (DCs) generated in the presence of IL-4/GM-CSF (IL4-DCs) and IFNα/GM-CSF (IFN-DCs). We showed that IFN-DCs displayed semi-mature phenotype and expressed higher level of CD123, TNF-related apoptosis-inducing ligand (TRAIL) and B7-H1 molecules in comparison with IL4-DCs. LPS-stimulated IFN-DCs were characterized by greater production of Th1/pro-inflammatory (IFN-γ, IL-2, IL-1β, TNF-α, IL-17), Тh2/anti-inflammatory cytokines (IL-10, IL-5), hematopoietic growth factors (G-CSF) and chemokines (MCP-1). These data indicated more pronounced ability of IFN-DCs to induce cellular immune response as well as humoral immune response compared to IL4-DCs. LPS-stimulated IFN-DCs possessed higher direct cytotoxic activity against TRAIL-sensitive tumor cell line Jurkat and similar cytotoxicity against TRAIL-resistant tumor HEp-2 cells. Besides, IFN-DCs and IL4-DCs equally induced apoptosis of activated CD4(+) and CD8(+) T cells. These results suggest that IFN-DCs can be used as potent cell-based curative therapies for individuals with cancer.
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Affiliation(s)
- Olga Yu Leplina
- Institute of Clinical Immunology SB RAMS, 14 Yadrintsevskaya Str., 630099 Novosibirsk, Russia(1)
| | - Tamara V Tyrinova
- Institute of Clinical Immunology SB RAMS, 14 Yadrintsevskaya Str., 630099 Novosibirsk, Russia(1).
| | - Marina A Tikhonova
- Institute of Clinical Immunology SB RAMS, 14 Yadrintsevskaya Str., 630099 Novosibirsk, Russia(1)
| | - Alexander A Ostanin
- Institute of Clinical Immunology SB RAMS, 14 Yadrintsevskaya Str., 630099 Novosibirsk, Russia(1)
| | - Elena R Chernykh
- Institute of Clinical Immunology SB RAMS, 14 Yadrintsevskaya Str., 630099 Novosibirsk, Russia(1)
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26
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Leone P, Di Tacchio M, Berardi S, Santantonio T, Fasano M, Ferrone S, Vacca A, Dammacco F, Racanelli V. Dendritic cell maturation in HCV infection: altered regulation of MHC class I antigen processing-presenting machinery. J Hepatol 2014; 61:242-51. [PMID: 24732300 PMCID: PMC8759579 DOI: 10.1016/j.jhep.2014.04.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Revised: 03/04/2014] [Accepted: 04/06/2014] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Modulation of dendritic cell (DC) function has been theorized as one of the mechanisms used by hepatitis C virus (HCV) to evade the host immune response and cause persistent infection. METHODS We used a range of cell and molecular biology techniques to study DC subsets from uninfected and HCV-infected individuals. RESULTS We found that patients with persistent HCV infection have lower numbers of circulating myeloid DC and plasmacytoid DC than healthy controls or patients who spontaneously recovered from HCV infection. Nonetheless, DC from patients with persistent HCV infection display normal phagocytic activity, typical expression of the class I and II HLA and co-stimulatory molecules, and conventional cytokine production when stimulated to mature in vitro. In contrast, they do not display the strong switch from immunoproteasome to standard proteasome subunit expression and the upregulation of the transporter-associated proteins following stimulation, which were instead observed in DC from uninfected individuals. This different modulation of components of the HLA class I antigen processing-presenting machinery results in a differential ability to present a CD8(+) T cell epitope whose generation is dependent on the LMP7 immunoproteasome subunit. CONCLUSIONS Overall, these findings establish that under conditions of persistent HCV antigenemia, HLA class I antigen processing and presentation are distinctively regulated during DC maturation.
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Affiliation(s)
- Patrizia Leone
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Mariangela Di Tacchio
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Simona Berardi
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | | | - Massimo Fasano
- Department of Infectious Diseases, University of Foggia, Foggia, Italy
| | - Soldano Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Angelo Vacca
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Franco Dammacco
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Vito Racanelli
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy.
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Abstract
Persistent viral infection, such as HCV infection, is the result of the inability of the host immune system to mount a successful antiviral response, as well as the escape strategies devised by the virus. Although each individual component of the host immune system plays important roles in antiviral immunity, the interactive network of immune cells as a whole acts against the virus. The innate immune system forms the first line of host defense against viral infection, and thus, virus elimination or chronic HCV infection is linked to the direct outcome of the interactions between the various innate immune cells and HCV. By understanding how the distinct components of the innate immune system function both individually and collectively during HCV infection, potential therapeutic targets can be identified to overcome immune dysfunction and control chronic viral infection.
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Affiliation(s)
- Banishree Saha
- University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Gyongyi Szabo
- University of Massachusetts Medical School, Worcester, Massachusetts, USA
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28
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Sehgal M, Zeremski M, Talal AH, Khan ZK, Capocasale R, Philip R, Jain P. Host Genetic Factors and Dendritic Cell Responses Associated with the Outcome of Interferon/Ribavirin Treatment in HIV-1/HCV Co-Infected Individuals. ACTA ACUST UNITED AC 2014; 5. [PMID: 25705565 PMCID: PMC4332701 DOI: 10.4172/2155-9899.1000271] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
HIV-1/HCV co-infection is a significant health problem. Highly active antiretroviral treatment (HAART) against HIV-1 has proved to be fairly successful. On the other hand, direct acting antiviral drugs against HCV have improved cure rates but high cost and development of drug resistance are important concerns. Therefore PEGylated interferon (PEG-IFN) and ribavirin (RBV) still remain essential components of HCV treatment, and identification of host factors that predict IFN/RBV treatment response is necessary for effective clinical management of HCV infection. Impaired dendritic cell (DC) and T cell responses are associated with HCV persistence. It has been shown that IFN/RBV treatment enhances HCV-specific T cell functions and it is likely that functional restoration of DCs is the underlying cause. To test this hypothesis, we utilized an antibody cocktail (consisting of DC maturation, adhesion and other surface markers) to perform comprehensive phenotypic characterization of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in a cohort of HIV-1/HCV co-infected individuals undergoing IFN/RBV treatment. Our results show that pre-treatment frequencies of mDCs are lower in non-responders (NRs) compared to responders (SVRs) and healthy controls. Although, the treatment was able to restore the frequency of mDCs in NRs, it downregulated the frequency of CCR7+, CD54+ and CD62L+ mDCs. Pre-treatment frequencies of pDCs were lower in NRs and decreased further upon treatment. Compared to SVRs, NRs exhibited higher ratio of PD-L1+/CD86+ pDCs prior to treatment; and this ratio remained high even after treatment. These findings demonstrate that enumeration and phenotypic assessment of DCs before/during therapy can help predict the treatment outcome. We also show that before treatment, PBMCs from SVRs secrete higher amounts of IFN-γ compared to controls and NRs. Upon genotyping IFNL3 polymorphisms rs12979860, rs4803217 and ss469415590, we found rs12979860 to be a better predictor of treatment outcome. Collectively, our study led to identification of important correlates of IFN/RBV treatment response in HIV-1/HCV co-infected individuals.
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Affiliation(s)
- Mohit Sehgal
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Marija Zeremski
- School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Andrew H Talal
- School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Zafar K Khan
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Renold Capocasale
- Flowmetric, Inc., Pennsylvania Biotechnology Center, Doylestown, PA, USA
| | - Ramila Philip
- Immunotope, Inc., Pennsylvania Biotechnology Center, Doylestown, PA, USA
| | - Pooja Jain
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
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Pelletier S, Bédard N, Said E, Ancuta P, Bruneau J, Shoukry NH. Sustained hyperresponsiveness of dendritic cells is associated with spontaneous resolution of acute hepatitis C. J Virol 2013; 87:6769-81. [PMID: 23576504 PMCID: PMC3676083 DOI: 10.1128/jvi.02445-12] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2012] [Accepted: 03/25/2013] [Indexed: 12/11/2022] Open
Abstract
Some studies have reported that dendritic cells (DCs) may be dysfunctional in a subset of patients with chronic hepatitis C virus (HCV) infection. However, the function of DCs during acute HCV infection and their role in determining infectious outcome remain elusive. Here, we examined the phenotype and function of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) during acute HCV infection. Three groups of injection drug users (IDUs) at high risk of HCV infection were studied: an uninfected group, a group with acute HCV infection with spontaneous resolution, and a group with acute infection with chronic evolution. We examined the frequency, maturation status, and cytokine production capacity of DCs in response to the Toll-like receptor 4 (TLR4) and TLR7/8 ligands lipopolysaccharide (LPS) and single-stranded RNA (ssRNA), respectively. Several observations could distinguish HCV-negative IDUs and acute HCV resolvers from patients with acute infection with chronic evolution. First, we observed a decrease in the frequency of mature CD86(+), programmed death-1 receptor ligand-positive (PDL1(+)), and PDL2(+) pDCs. This phenotype was associated with the increased sensitivity of pDCs from resolvers and HCV-negative IDUs versus the group with acute infection with chronic evolution to ssRNA stimulation in vitro. Second, LPS-stimulated mDCs from resolvers and HCV-negative IDUs produced higher levels of cytokines than mDCs from the group with acute infection with chronic evolution. Third, mDCs from all patients with acute HCV infection, irrespective of their outcomes, produced higher levels of cytokines during the early acute phase in response to ssRNA than mDCs from healthy controls. However, this hyperresponsiveness was sustained only in spontaneous resolvers. Altogether, our results suggest that the immature pDC phenotype and sustained pDC and mDC hyperresponsiveness are associated with spontaneous resolution of acute HCV infection.
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Affiliation(s)
- Sandy Pelletier
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital St-Luc,
- Département de Microbiologie et Immunologie,
| | - Nathalie Bédard
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital St-Luc,
| | - Elias Said
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital St-Luc,
- Département de Microbiologie et Immunologie,
| | - Petronela Ancuta
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital St-Luc,
- Département de Microbiologie et Immunologie,
| | - Julie Bruneau
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital St-Luc,
- Département de Médecine Familiale,
| | - Naglaa H. Shoukry
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital St-Luc,
- Département de Médecine, Université de Montréal, Montréal, Quebec, Canada
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30
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Self AA, Losikoff PT, Gregory SH. Divergent contributions of regulatory T cells to the pathogenesis of chronic hepatitis C. Hum Vaccin Immunother 2013; 9:1569-76. [PMID: 23732899 DOI: 10.4161/hv.24726] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Hepatitis C virus, a small single-stranded RNA virus, is a major cause of chronic liver disease. Resolution of primary hepatitis C virus infections depends upon the vigorous responses of CD4(+) and CD8(+) T cells to multiple viral epitopes. Although such broad CD4(+) and CD8(+) T-cell responses are readily detected early during the course of infection regardless of clinical outcome, they are not maintained in individuals who develop chronic disease. Purportedly, a variety of factors contribute to the diminished T-cell responses observed in chronic, virus-infected patients including the induction of and biological suppression by CD4(+)FoxP3(+) regulatory T cells. Indeed, a wealth of evidence suggests that regulatory T cells play diverse roles in the pathogenesis of chronic hepatitis C, impairing the effector T-cell response and viral clearance early during the course of infection and suppressing liver injury as the disease progresses. The factors that affect the generation and biological response of regulatory T cells in chronic, hepatitis C virus-infected patients is discussed.
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Affiliation(s)
- Ayssa A Self
- Department of Medicine; Rhode Island Hospital and the Warren Alpert Medical School of Brown University; Providence, RI USA
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31
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Abstract
Hepatitis C virus (HCV) is a major cause of chronic hepatitis and hepatocellular carcinoma worldwide. Due to shared transmission routes, the prevalence of HCV is especially high among individuals infected with HIV. HIV uninfected individuals spontaneously clear HCV approximately 30 % of the time, while the rate of control in HIV infected individuals who subsequently acquire HCV is substantially lower. In addition, complications of HCV are more frequent in those with HIV infection, making liver disease the leading cause of non-AIDS-related death in HIV infected individuals. This review summarizes recent advances in understanding the role of the innate and adaptive immune responses to HCV in those with and without HIV. Further defining the interaction between hepatitis C and the host immune system will potentially reveal insights into HCV pathogenesis and the host's ability to prevent persistent infection, as well as direct the development of vaccines.
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Affiliation(s)
- Rebecca R Terilli
- Division of Infectious Diseases, Johns Hopkins University School of Medicine, Rangos Building, Suite 536, 855 N Wolfe St, Baltimore, MD 21205, USA
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32
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Sehgal M, Khan ZK, Talal AH, Jain P. Dendritic Cells in HIV-1 and HCV Infection: Can They Help Win the Battle? Virology (Auckl) 2013; 4:1-25. [PMID: 25512691 PMCID: PMC4222345 DOI: 10.4137/vrt.s11046] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Persistent infections with human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) are a major cause of morbidity and mortality worldwide. As sentinels of our immune system, dendritic cells (DCs) play a central role in initiating and regulating a potent antiviral immune response. Recent advances in our understanding of the role of DCs during HIV-1 and HCV infection have provided crucial insights into the mechanisms employed by these viruses to impair DC functions in order to evade an effective immune response against them. Modulation of the immunological synapse between DC and T-cell, as well as dysregulation of the crosstalk between DCs and natural killer (NK) cells, are emerging as two crucial mechanisms. This review focuses on understanding the interaction of HIV-1 and HCV with DCs not only to understand the immunopathogenesis of chronic HIV-1 and HCV infection, but also to explore the possibilities of DC-based immunotherapeutic approaches against them. Host genetic makeup is known to play major roles in infection outcome and rate of disease progression, as well as response to anti-viral therapy in both HIV-1 and HCV-infected individuals. Therefore, we highlight the genetic variations that can potentially affect DC functions, especially in the setting of chronic viral infection. Altogether, we address if DCs’ potential as critical effectors of antiviral immune response could indeed be utilized to combat chronic infection with HIV-1 and HCV.
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Affiliation(s)
- Mohit Sehgal
- Department of Microbiology and Immunology, and the Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
| | - Zafar K Khan
- Department of Microbiology and Immunology, and the Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
| | - Andrew H Talal
- Center for the Study of Hepatitis C, Weill Cornell Medical College, New York, NY
| | - Pooja Jain
- Department of Microbiology and Immunology, and the Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
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Hajarizadeh B, Grebely J, Dore GJ. Case definitions for acute hepatitis C virus infection: a systematic review. J Hepatol 2012; 57:1349-60. [PMID: 22796896 DOI: 10.1016/j.jhep.2012.07.007] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Revised: 07/03/2012] [Accepted: 07/05/2012] [Indexed: 01/18/2023]
Abstract
BACKGROUND & AIMS Case definitions for recent hepatitis C virus (HCV) infection vary considerably between studies. The aim of this systematic review was to characterize case definitions for recent HCV and explore the heterogeneity in studies performed to date. METHODS A systematic literature search of MEDLINE, SCOPUS, and ISI Web of Knowledge was performed covering all studies of recent HCV infection cited between January 2000 and June 2011. The criteria used by each study to define cases of recent HCV infection were extracted, structured, and analyzed. RESULTS Overall, 195 articles were included, with 87% (n=169) providing a clear case definition for recent HCV infection. The most frequently used individual criteria for defining a case included HCV antibody seroconversion (77%), alanine aminotransferase (ALT) elevation (68%), and HCV RNA detection (63%). In studies using HCV antibody seroconversion, the window period between the last negative and the first positive antibody test varied widely across studies (4 weeks to 4 years). Considerable diversity was also observed with respect to the ALT threshold used to characterize ALT elevations, ranging from 2 to 20 times the upper limit of normal. HCV antibody seroconversion was used as a single criterion in 41% of the studies, while all other studies used at least two criteria (range: 2-9). Epidemiology/surveillance studies mostly used a more sensitive case definition, whereas treatment studies, natural history studies, and diagnosis studies used more specific case definitions. CONCLUSIONS Marked heterogeneity in case definitions for recent HCV infection was observed. Although a single case definition for recent HCV is not warranted, a degree of standardization within specific study categories would enable improved cross-study comparison and more uniform evaluation of HCV prevention and management strategies.
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Affiliation(s)
- Behzad Hajarizadeh
- Viral Hepatitis Clinical Research Program, The Kirby Institute, The University of New South Wales (UNSW), Sydney, NSW, Australia.
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34
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Losikoff PT, Self AA, Gregory SH. Dendritic cells, regulatory T cells and the pathogenesis of chronic hepatitis C. Virulence 2012; 3:610-20. [PMID: 23076334 PMCID: PMC3545943 DOI: 10.4161/viru.21823] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) is a small, enveloped RNA virus and a major cause of chronic liver disease. Resolution of primary HCV infections depends upon the vigorous responses of CD4+ and CD8+ T cells to multiple viral epitopes. Although such broad-based responses are readily detected early during the course of infection regardless of clinical outcome, they are not maintained in individuals who develop chronic disease. Ostensibly, a variety of factors contribute to the diminished T cell responses observed in chronic, HCV-infected patients including impaired dendritic cell function and the induction of CD4+FoxP3+ regulatory T cells. Overwhelming evidence suggests that the complex interaction of dendritic cells and regulatory T cells plays a critical role in the pathogenesis of chronic hepatitis C.
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Affiliation(s)
- Phyllis T Losikoff
- Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School at Brown University, Providence, RI, USA
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35
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Zhou Y, Zhang Y, Yao Z, Moorman JP, Jia Z. Dendritic cell-based immunity and vaccination against hepatitis C virus infection. Immunology 2012; 136:385-96. [PMID: 22486354 DOI: 10.1111/j.1365-2567.2012.03590.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) has chronically infected an estimated 170 million people worldwide. There are many impediments to the development of an effective vaccine for HCV infection. Dendritic cells (DC) remain the most important antigen-presenting cells for host immune responses, and are capable of either inducing productive immunity or maintaining the state of tolerance to self and non-self antigens. Researchers have recently explored the mechanisms by which DC function is regulated during HCV infection, leading to impaired antiviral T-cell responses and so to persistent viral infection. Recently, DC-based vaccines against HCV have been developed. This review summarizes the current understanding of DC function during HCV infection and explores the prospects of DC-based HCV vaccine. In particular, it describes the biology of DC, the phenotype of DC in HCV-infected patients, the effect of HCV on DC development and function, the studies on new DC-based vaccines against HCV infection, and strategies to improve the efficacy of DC-based vaccines.
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Affiliation(s)
- Yun Zhou
- Centre of Diagnosis and Treatment for Infectious Diseases of Chinese PLA, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China
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36
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Abstract
The immune response in patients chronically infected with HCV plays a unique role during the infection because of its potential to contribute not only to viral clearance and, in some cases, protective immunity, but also to liver injury. A detailed understanding of the immunological mechanisms involved in persistence to HCV is essential to fully appreciate the complexity of the disease. In recent years, enormous progress has been made to characterize the dysfunctional natural killer cells and T cells during the chronic phase of infection. This information is important to further optimize treatment strategies based on the strengthening antiviral and immunomodulatory activities in patients chronically infected with HCV.
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Affiliation(s)
- Michelle Spaan
- Liver Unit, Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
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37
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Guo Z, Zhang H, Rao H, Jiang D, Cong X, Feng B, Wang J, Wei L, Chen H. DCs pulsed with novel HLA-A2-restricted CTL epitopes against hepatitis C virus induced a broadly reactive anti-HCV-specific T lymphocyte response. PLoS One 2012; 7:e38390. [PMID: 22701633 PMCID: PMC3373515 DOI: 10.1371/journal.pone.0038390] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Accepted: 05/04/2012] [Indexed: 12/28/2022] Open
Abstract
Objective To determine the capacity of dendritic cells (DCs) loaded with single or multiple-peptide mixtures of novel hepatitis C virus (HCV) epitopes to stimulate HCV-specific cytotoxic T lymphocyte (CTL) effector functions. Methods A bioinformatics approach was used to predict HLA-A2-restricted HCV-specific CTL epitopes, and the predicted peptides identified from this screen were synthesized. Subsequent IFN-γ ELISPOT analysis detected the stimulating function of these peptides in peripheral blood mononuclear cells (PBMCs) from both chronic and self-limited HCV infected subjects (subjects exhibiting spontaneous HCV clearance). Mature DCs, derived in vitro from CD14+ monocytes harvested from the study subjects by incubation with appropriate cytokine cocktails, were loaded with novel peptide or epitope peptide mixtures and co-cultured with autologous T lymphocytes. Granzyme B (GrB) and IFN-γ ELISPOT analysis was used to test for epitope-specific CTL responses. T-cell-derived cytokines contained in the co-cultured supernatant were detected by flow cytometry. Results We identified 7 novel HLA-A2-restricted HCV-specific CTL epitopes that increased the frequency of IFN-γ-producing T cells compared to other epitopes, as assayed by measuring spot forming cells (SFCs). Two epitopes had the strongest stimulating capability in the self-limited subjects, one found in the E2 and one in the NS2 region of HCV; five epitopes had a strong stimulating capacity in both chronic and self-limited HCV infection, but were stronger in the self-limited subjects. They were distributed in E2, NS2, NS3, NS4, and NS5 regions of HCV, respectively. We also found that mDCs loaded with novel peptide mixtures could significantly increase GrB and IFN-γ SFCs as compared to single peptides, especially in chronic HCV infection subjects. Additionally, we found that DCs pulsed with multiple epitope peptide mixtures induced a Th1-biased immune response. Conclusions Seven novel and strongly stimulating HLA-A2-restricted HCV-specific CTL epitopes were identified. Furthermore, DCs loaded with multiple-epitope peptide mixtures induced epitope-specific CTLs responses.
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Affiliation(s)
- Zhongsheng Guo
- Hepatology Institute, Peking University, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Henghui Zhang
- Hepatology Institute, Peking University, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Huiying Rao
- Hepatology Institute, Peking University, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Dong Jiang
- Hepatology Institute, Peking University, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Xu Cong
- Hepatology Institute, Peking University, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Bo Feng
- Hepatology Institute, Peking University, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Jianghua Wang
- Hepatology Institute, Peking University, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Lai Wei
- Hepatology Institute, Peking University, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
- * E-mail:
| | - Hongsong Chen
- Hepatology Institute, Peking University, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
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38
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Glances in Immunology of HIV and HCV Infection. Adv Virol 2012; 2012:434036. [PMID: 22754568 PMCID: PMC3375159 DOI: 10.1155/2012/434036] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2012] [Accepted: 03/12/2012] [Indexed: 12/16/2022] Open
Abstract
Since the identification of HIV and HCV much progress has been made in the understanding of their life cycle and interaction with the host immune system. Despite these viruses markedly differ in their virological properties and in their pathogenesis, they share many common features in their immune escape and survival strategy. Both viruses have developed sophisticated ways to subvert and antagonize host innate and adaptive immune responses. In the last years, much effort has been done in the study of the AIDS pathogenesis and in the development of efficient treatment strategies, and a fatal infection has been transformed in a potentially chronic pathology. Much of this knowledge is now being transferred in the HCV research field, especially in the development of new drugs, although a big difference still remains between the outcome of the two infections, being HCV eradicable after treatment, whereas HIV eradication remains at present unachievable due to the establishment of reservoirs. In this review, we present current knowledge on innate and adaptive immune recognition and activation during HIV and HCV mono-infections and evasion strategies. We also discuss the genetic associations between components of the immune system, the course of infection, and the outcome of the therapies.
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Abstract
Cytokines are intercellular mediators involved in viral control and liver damage being induced by infection with hepatitis C virus (HCV). The complex cytokine network operating during initial infection allows a coordinated, effective development of both innate and adaptive immune responses. However, HCV interferes with cytokines at various levels and escapes immune response by inducing a T-helper (Th)2/T cytotoxic 2 cytokine profile. Inability to control infection leads to the recruitment of inflammatory infiltrates into the liver parenchyma by interferon (IFN)-gamma-inducible CXC chemokine ligand (CXCL)-9, -10, and -11 chemokines, which results in sustained liver damage and eventually in liver cirrhosis. The most important systemic HCV-related extrahepatic diseases--mixed cryoglobulinemia, lymphoproliferative disorders, thyroid autoimmune disorders, and type 2 diabetes--are associated with a complex dysregulation of the cytokine/chemokine network, involving proinflammatory and Th1 chemokines. The therapeutical administration of cytokines such as IFN-alpha may result in viral clearance during persistent infection and reverts this process.
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40
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Zwolak A, Jastrzebska I, Surdacka A, Kasztelan-Szczerbińska B, Łozowski CT, Roliński J, Skrzydło-Radomańska B, Radwan P, Daniluk J. Peripheral blood dendritic cells in alcoholic and autoimmune liver disorders. Hum Exp Toxicol 2012; 31:438-446. [PMID: 22076495 DOI: 10.1177/0960327111426582] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Little is known about effects of alcohol consumption on dendritic cell (DC) function and resultant immune response. However, quantitative and qualitative disturbances of DCs are speculated to be involved in alcohol-related as well as in other liver pathology. The present study aimed to evaluate changes in circulating DC subsets in alcoholic liver disease (N = 43), autoimmune hepatitis (N = 26) and primary biliary cirrhosis (N = 20). DCs isolated from the peripheral blood of recruited participants were stained with monoclonal antibodies against blood dendritic cell antigens (BDCAs) and estimated using the flow cytometry. Myeloid DCs were defined as BDCA-1(+)/CD19(-) cells, and lymphoid DCs as BDCA-2(+)/CD123(+) cells. Total numbers of circulating DCs in subjects with some liver diseases were markedly lower than in the healthy participants (p = 0.03). There was a significantly lower percentage of circulating BDCA-2(+)/CD123(+) (p = 0.02), and a tendency for the percentage of circulating BDCA-1(+)/CD19(-) cells to decrease in patients with liver diseases compared to the controls (p = 0.09). These results may suggest that decreased numbers of DCs may be responsible for reduced adaptive immune responses and increased susceptibility to infections and cancer development observed in patients exposed to alcohol. Moreover, numerical abnormalities of DCs may contribute to the breakdown of self-tolerance, a feature of autoimmune diseases.
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Affiliation(s)
- A Zwolak
- Department of Internal Medicine and Internal Medicine in Nursing, Medical University of Lublin, Poland.
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41
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Varani S, Rossini G, Mastroianni A, Tammik C, Frascaroli G, Landini MP, Castellani G, Söderberg-Nauclér C. High TNF-alpha and IL-8 levels predict low blood dendritic cell counts in primary cytomegalovirus infection. J Clin Virol 2012; 53:360-363. [PMID: 22257833 DOI: 10.1016/j.jcv.2011.12.028] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2011] [Revised: 12/22/2011] [Accepted: 12/23/2011] [Indexed: 01/10/2023]
Abstract
BACKGROUND In vitro studies suggest that human cytomegalovirus (CMV) modulates the functions of dendritic cells (DCs). However, there are limited data on DC homeostasis in CMV-infected patients. OBJECTIVES The aim of this study was to characterize circulating DCs and plasma cytokine levels in immunocompetent patients with primary, symptomatic CMV infections. STUDY DESIGN The study population consisted of 14 patients suffering of CMV mononucleosis and 14 healthy volunteers (11 CMV-seropositive and 3 CMV-seronegative subjects) included as controls. Peripheral blood mononuclear cells were isolated and used to characterize DCs and to quantify CMV in the blood. Plasma levels of pro-inflammatory and anti-inflammatory cytokines were also measured. RESULTS We observed that patients who were developing CMV mononucleosis presented lower myeloid and plasmacytoid DC counts in peripheral blood compared with healthy controls. We also noted elevated levels of inflammatory mediators, of which tumor necrosis factor-α (TNF-α)-which activates DCs and endothelial cells-was the highest. Notably, the decrease in blood DCs correlated with high TNF-α and IL-8 levels by a hyperbolic function. CONCLUSIONS Our results suggest that increased levels of inflammatory factors facilitate alterations in DC homeostasis during primary CMV infection, which may contribute to viral-induced modulation of host immunity.
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Affiliation(s)
- Stefania Varani
- Department of Hematology and Oncology L&A Seragnoli, University of Bologna, Italy.
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42
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Burlone ME, Minisini R, Pirisi M. Interferon-stimulated gene pathways in the treatment of viral hepatitis. Future Virol 2012. [DOI: 10.2217/fvl.12.21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Viral hepatitis has been treated empirically for more than 30 years with interferon (IFN)-based therapies, although in the early days of the IFN era, very little was known regarding the mechanisms of action through which IFN acts and the strategies that viruses deploy to escape the antiviral state induced by the activation of the IFN system. Over the years, we have learned how key effector molecules in this system are expressed and interact. On the verge of novel, IFN-free regimens for viral hepatitis, we can take advantage of this huge bulk of research data in order to gain better understanding of how resistance to IFN develops in our patients, to use IFN more effectively in conjunction with other drugs and to devise new treatments.
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Affiliation(s)
- Michela E Burlone
- Dipartimento di Medicina Traslazionale, Università del Piemonte Orientale ‘Amedeo Avogadro’, Novara, Italy
| | - Rosalba Minisini
- Dipartimento di Medicina Traslazionale, Università del Piemonte Orientale ‘Amedeo Avogadro’, Novara, Italy
| | - Mario Pirisi
- Dipartimento di Medicina Traslazionale, Università del Piemonte Orientale ‘Amedeo Avogadro’, Novara, Italy
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43
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Goutagny N, Estornes Y, Hasan U, Lebecque S, Caux C. Targeting pattern recognition receptors in cancer immunotherapy. Target Oncol 2012; 7:29-54. [PMID: 22399234 DOI: 10.1007/s11523-012-0213-1] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2011] [Accepted: 01/13/2012] [Indexed: 12/20/2022]
Abstract
Pattern recognition receptors (PRRs) are known for many years for their role in the recognition of microbial products and the subsequent activation of the immune system. The 2011 Nobel Prize for medicine indeed rewarded J. Hoffmann/B. Beutler and R. Steinman for their revolutionary findings concerning the activation of the immune system, thus stressing the significance of understanding the mechanisms of activation of the innate immunity. Such immunostimulatory activities are of major interest in the context of cancer to induce long-term antitumoral responses. Ligands for the toll-like receptors (TLRs), a well-known family of PRR, have been shown to have antitumoral activities in several cancers. Those ligands are now undergoing extensive clinical investigations both as immunostimulant molecules and as adjuvant along with vaccines. However, when considering the use of these ligands in tumor therapy, one shall consider the potential effect on the tumor cells themselves as well as on the entire organism. Recent data indeed demonstrate that TLR activation in tumor cells could trigger both pro- or antitumoral effect depending on the context. This review discusses this balance between the intrinsic activation of PRR in tumor cells and the extrinsic microenvironment activation in term of overall effect of PRR ligands on tumor development. We review recent advances in the field and underline appealing prospects for clinical development of PRR agonists in the light of our current knowledge on their expression and activation.
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Affiliation(s)
- Nadège Goutagny
- Université de Lyon, Université Lyon I, UMR INSERM 1052 CNRS 5286, Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, Lyon, France.
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44
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Pasetto A, Frelin L, Brass A, Yasmeen A, Koh S, Lohmann V, Bartenschlager R, Magalhaes I, Maeurer M, Sällberg M, Chen M. Generation of T-cell receptors targeting a genetically stable and immunodominant cytotoxic T-lymphocyte epitope within hepatitis C virus non-structural protein 3. J Gen Virol 2011; 93:247-258. [PMID: 22071510 PMCID: PMC3352347 DOI: 10.1099/vir.0.037903-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) is a major cause of severe liver disease, and one major contributing factor is thought to involve a dysfunction of virus-specific T-cells. T-cell receptor (TCR) gene therapy with HCV-specific TCRs would increase the number of effector T-cells to promote virus clearance. We therefore took advantage of HLA-A2 transgenic mice to generate multiple TCR candidates against HCV using DNA vaccination followed by generation of stable T-cell–BW (T-BW) tumour hybrid cells. Using this approach, large numbers of non-structural protein 3 (NS3)-specific functional T-BW hybrids can be generated efficiently. These predominantly target the genetically stable HCV genotype 1 NS31073–1081 CTL epitope, frequently associated with clearance of HCV in humans. These T-BW hybrid clones recognized the NS31073 peptide with a high avidity. The hybridoma effectively recognized virus variants and targeted cells with low HLA-A2 expression, which has not been reported previously. Importantly, high-avidity murine TCRs effectively redirected human non-HCV-specific T-lymphocytes to recognize human hepatoma cells with HCV RNA replication driven by a subgenomic HCV replicon. Taken together, TCR candidates with a range of functional avidities, which can be used to study immune recognition of HCV-positive targets, have been generated. This has implications for TCR-related immunotherapy against HCV.
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Affiliation(s)
- Anna Pasetto
- Department of Laboratory Medicine, Stockholm, Sweden.,Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Lars Frelin
- Department of Laboratory Medicine, Stockholm, Sweden
| | - Anette Brass
- Department of Laboratory Medicine, Stockholm, Sweden
| | - Anila Yasmeen
- Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Sarene Koh
- Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore.,Department of Laboratory Medicine, Stockholm, Sweden
| | - Volker Lohmann
- Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Germany
| | - Ralf Bartenschlager
- Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Germany
| | - Isabelle Magalhaes
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet and Swedish Institute for Infectious Disease Control, Stockholm, Sweden
| | - Markus Maeurer
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet and Swedish Institute for Infectious Disease Control, Stockholm, Sweden
| | | | - Margaret Chen
- Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden
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45
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Vincent IE, Zannetti C, Lucifora J, Norder H, Protzer U, Hainaut P, Zoulim F, Tommasino M, Trépo C, Hasan U, Chemin I. Hepatitis B virus impairs TLR9 expression and function in plasmacytoid dendritic cells. PLoS One 2011; 6:e26315. [PMID: 22046272 PMCID: PMC3201951 DOI: 10.1371/journal.pone.0026315] [Citation(s) in RCA: 125] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2010] [Accepted: 09/23/2011] [Indexed: 12/18/2022] Open
Abstract
Plasmacytoid dendritic cells (pDCs) play a key role in detecting pathogens by producing large amounts of type I interferon (IFN) by sensing the presence of viral infections through the Toll-Like Receptor (TLR) pathway. TLR9 is a sensor of viral and bacterial DNA motifs and activates the IRF7 transcription factor which leads to type I IFN secretion by pDCs. However, during chronic hepatitis B virus (HBV) infection, pDCs display an impaired ability to secrete IFN-α following ex vivo stimulation with TLR9 ligands. Here we highlight several strategies used by HBV to block IFN-α production through a specific impairment of the TLR9 signaling. Our results show that HBV particle internalisation could inhibit TLR9- but not TLR7-mediated secretion of IFN-α by pDCs. We observed that HBV down-regulated TLR9 transcriptional activity in pDCs and B cells in which TLR9 mRNA and protein levels were reduced. HBV can interfere with TLR9 activity by blocking the MyD88-IRAK4 axis and Sendai virus targeting IRF7 to block IFN-α production. Neutralising CpG motif sequences were identified within HBV DNA genome of genotypes A to H which displayed a suppressive effect on TLR9-immune activation. Moreover, TLR9 mRNA and protein were downregulated in PBMCs from patients with HBV-associated chronic hepatitis and hepatocellular carcinoma. Thus HBV has developed several escape mechanisms to avoid TLR9 activation in both pDCs and B lymphocytes, which may in turn contribute to the establishment and/or persistence of chronic infection.
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46
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Ryan EJ, O'Farrelly C. The affect of chronic hepatitis C infection on dendritic cell function: a summary of the experimental evidence. J Viral Hepat 2011; 18:601-7. [PMID: 21794024 DOI: 10.1111/j.1365-2893.2011.01453.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Chronic hepatitis C virus (HCV) infection occurs in patients who fail to mount an effective T-cell response against the virus. One hypothesis for poor anti-viral immunity in these patients is that the virus impedes the immune response by disabling dendritic cells (DCs), cells that play a key role in pathogen recognition and initiation of adaptive immunity. Initial studies in the 1990s supported this hypothesis, as they clearly demonstrated that monocyte-derived DCs obtained from patients with chronic HCV infection displayed a reduced ability to stimulate lymphocyte proliferation. However, over the last 20 years, the situation has become more ambiguous. Many studies support the initial observation of a DC defect, while others using different patient cohorts or technologies have clearly demonstrated intact DC function in patients with chronic HCV. It is likely that the true situation lies somewhere in between. Just as there is a spectrum of disease in patients with chronic HCV, DCs obtained from different patients may display different properties. It is important to reconcile these divergent findings, as a clearer understanding of how the virus affects DC function will facilitate the development of immunotherapy and therapeutic vaccination strategies for patients with chronic HCV infection.
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Affiliation(s)
- E J Ryan
- School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland.
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47
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Nellore A, Fishman JA. NK cells, innate immunity and hepatitis C infection after liver transplantation. Clin Infect Dis 2011; 52:369-77. [PMID: 21217184 DOI: 10.1093/cid/ciq156] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Liver transplantation in patients with active hepatitis C virus (HCV) infection is followed by almost universal recurrence of viral infection. The control of HCV infection has been characterized largely in terms of the HCV-specific function of T-lymphocytes and the adaptive immune response. Emerging data suggest that components of the innate immune system, including natural killer cells, have a central role in determining the nature of posttransplant HCV infection and the likelihood of response to antiviral therapy. This review examines the emerging evidence implicating innate immunity in the pathogenesis of posttransplant HCV infections and the potential therapeutic implications of these observations.
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Affiliation(s)
- Anoma Nellore
- Infectious Disease Division and Transplant Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
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48
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Dolganiuc A, Szabo G. Dendritic cells in hepatitis C infection: can they (help) win the battle? J Gastroenterol 2011; 46:432-47. [PMID: 21327958 DOI: 10.1007/s00535-011-0377-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2010] [Accepted: 12/13/2010] [Indexed: 02/04/2023]
Abstract
Infection with hepatitis C virus (HCV) is a public health problem; it establishes a chronic course in ~85% of infected patients and increases their risk for developing liver cirrhosis, hepatocellular carcinoma, and significant extrahepatic manifestations. The mechanisms of HCV persistence remain elusive and are largely related to inefficient clearance of the virus by the host immune system. Dendritic cells (DCs) are the most efficient inducers of immune responses; they are capable of triggering productive immunity and maintaining the state of tolerance to self- and non-self antigens. During the past decade, multiple research groups have focused on DCs, in hopes of unraveling an HCV-specific DC signature or DC-dependent mechanisms of antiviral immunity which would lead to a successful HCV elimination strategy. This review incorporates the latest update in the current status of knowledge on the role of DCs in anti-HCV immunity as it relates to several challenging questions: (a) the phenotype and function of diverse DC subsets in HCV-infected patients; (b) the characteristics of non-human HCV infection models from the DCs' point of view; (c) how can in vitro systems, ranging from HCV protein- or peptide-exposed DC to HCV protein-expressing DCs, and in vivo systems, ranging from HCV protein-expressing transgenic mice to HCV-infected non-human primates, be employed to dissect the role of DCs in triggering/maintaining a robust antiviral response; and (d) the prospect of DC-based strategy for managing and finding a cure for HCV infection.
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Affiliation(s)
- Angela Dolganiuc
- Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, LRB-270-H, Worcester, MA 01605, USA.
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49
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Washburn ML, Bility MT, Zhang L, Kovalev GI, Buntzman A, Frelinger JA, Barry W, Ploss A, Rice CM, Su L. A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease. Gastroenterology 2011; 140:1334-44. [PMID: 21237170 PMCID: PMC3066273 DOI: 10.1053/j.gastro.2011.01.001] [Citation(s) in RCA: 232] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2010] [Revised: 12/21/2010] [Accepted: 01/10/2011] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Studies of hepatitis C virus (HCV) infection, immunopathogenesis, and resulting liver diseases have been hampered by the lack of a small animal model. We developed humanized mice with human immune system and liver tissues to improve the studies of hepatitis C virus pathogenesis and treatment. METHODS To promote engraftment of human hepatocytes, we expressed a fusion protein of the FK506 binding protein (FKBP) and caspase 8 under control of the albumin promoter (AFC8), which induces liver cell death, in Balb/C Rag2(-/-) γC-null mice. Cotransplantation of human CD34(+) human hematopoietic stem cells (HSC) and hepatocyte progenitors into the transgenic mice led to efficient engraftment of human leukocytes and hepatocytes. We then infected these humanized mice (AFC8-hu HSC/Hep) with primary HCV isolates and studied HCV-induced immune responses and liver diseases. RESULTS AFC8-hu HSC/Hep mice supported HCV infection in the liver and generated a human immune T-cell response against HCV. HCV infection induced liver inflammation, hepatitis, and fibrosis, which correlated with activation of stellate cells and expression of human fibrogenic genes. CONCLUSIONS AFC8-hu HSC/Hep mice are a useful model of HCV infection, the immune response, and liver disease because they contain human immune system and liver cells. These mice become infected with HCV, generate a specific immune response against the virus, and develop liver diseases that include hepatitis and fibrosis. This model might also be used to develop therapeutics for HCV infection.
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Affiliation(s)
- Michael L. Washburn
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599,Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - Moses T. Bility
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - Liguo Zhang
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599,Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Grigoriy I. Kovalev
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - Adam Buntzman
- Departments of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - Jeffery A. Frelinger
- Departments of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - Walter Barry
- Center for the Study of Hepatitis C, The Rockefeller University, New York, New York, 10065 USA
| | - Alexander Ploss
- Center for the Study of Hepatitis C, The Rockefeller University, New York, New York, 10065 USA
| | - Charles M. Rice
- Center for the Study of Hepatitis C, The Rockefeller University, New York, New York, 10065 USA
| | - Lishan Su
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599,Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599,Departments of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599,Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
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50
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Viral replicative capacity is the primary determinant of lymphocytic choriomeningitis virus persistence and immunosuppression. Proc Natl Acad Sci U S A 2010; 107:21641-6. [PMID: 21098292 DOI: 10.1073/pnas.1011998107] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
The Clone 13 (Cl13) strain of lymphocytic choriomeningitis virus is widely studied as a model of chronic systemic viral infection. Here, we used reverse genetic techniques to identify the molecular basis of Cl13 persistence and immunosuppression, the characteristics differentiating it from the closely related Armstrong strain. We found that a single-point mutation in the Cl13 polymerase was necessary and partially sufficient for viral persistence and immunosuppression. A glycoprotein mutation known to enhance dendritic cell targeting accentuated both characteristics but when introduced alone, failed to alter the phenotype of the Armstrong strain. The decisive polymerase mutation increased intracellular viral RNA load in plasmacytoid dendritic cells, which we identified as a main initial target cell type in vivo, and increased viremia in the early phase of infection. These findings establish the enhanced replicative capacity as the primary determinant of the Cl13 phenotype. Viral persistence and immunosuppression can, thus, represent a direct consequence of excessive viral replication overwhelming the host's antiviral defense.
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