Multiple Mechanisms Contribute to Impairment of Type 1 Interferon Production during Chronic Lymphocytic Choriomeningitis Virus Infection of Mice1

Type 1 IFNs, innate cytokines with important effector and immunomodulatory properties, are rapidly induced in the acute phase of many virus infections; however, this is generally a transient response that is not sustained during virus persistence. To gain insight into mechanisms that can contribute to down-regulation of type 1 IFN production during virus persistence, we analyzed type 1 IFN production during acute and chronic lymphocytic choriomeningitis virus (LCMV) infection. High-level type 1 IFN production was transiently up-regulated in cells including plasmacytoid and conventional dendritic cells (DCs) following LCMV infection of mice, but LCMV persistence was associated with only low-level type 1 IFN production. Nonetheless, chronically infected mice were able to up-regulate type 1 IFN production in response to TLR3, 7, and 9 ligands, albeit less efficiently than uninfected mice. Splenic DC numbers in mice chronically infected with LCMV were decreased, and the remaining cells exhibited a reduced response to TLR stimulation. LCMV-infected cell lines efficiently up-regulated type 1 IFN production following TLR ligation and infection with a DNA virus, but exhibited a defect in type 1 IFN induction following infection with Sendai, an RNA virus. This block in type 1 IFN production by infected cells, together with abnormalities in DC numbers and functions, likely contribute to the low-level type 1 IFN production in mice chronically infected with LCMV. Impairment of type 1 IFN production may both promote virus persistence and impact on host immunocompetence. Understanding the mechanisms involved may assist in development of strategies for control of virus persistence and superinfection.

[1]  Osamu Takeuchi,et al.  MDA5/RIG-I and virus recognition. , 2008, Current opinion in immunology.

[2]  G. Lemke,et al.  TAM Receptors Are Pleiotropic Inhibitors of the Innate Immune Response , 2007, Cell.

[3]  S. Akira,et al.  Lymphocytoid Choriomeningitis Virus Activates Plasmacytoid Dendritic Cells and Induces a Cytotoxic T-Cell Response via MyD88 , 2007, Journal of Virology.

[4]  A. García-Sastre,et al.  Differential Inhibition of Type I Interferon Induction by Arenavirus Nucleoproteins , 2007, Journal of Virology.

[5]  A. Mansell,et al.  The negative regulation of Toll‐like receptor and associated pathways , 2007, Immunology and cell biology.

[6]  A. García-Sastre,et al.  Inhibition of the Type I Interferon Response by the Nucleoprotein of the Prototypic Arenavirus Lymphocytic Choriomeningitis Virus , 2006, Journal of Virology.

[7]  Jennifer Louten,et al.  Type 1 IFN Deficiency in the Absence of Normal Splenic Architecture during Lymphocytic Choriomeningitis Virus Infection1 , 2006, The Journal of Immunology.

[8]  P. Borrow,et al.  CD45 is required for type I IFN production by dendritic cells , 2006, European journal of immunology.

[9]  E. Peterhans,et al.  “Self” and “Nonself” Manipulation of Interferon Defense during Persistent Infection: Bovine Viral Diarrhea Virus Resists Alpha/Beta Interferon without Blocking Antiviral Activity against Unrelated Viruses Replicating in Its Host Cells , 2006, Journal of Virology.

[10]  Antonio Bertoletti,et al.  The immune response during hepatitis B virus infection. , 2006, The Journal of general virology.

[11]  D. Tough,et al.  Direct Stimulation of T Cells by Type I IFN Enhances the CD8+ T Cell Response during Cross-Priming1 , 2006, The Journal of Immunology.

[12]  C. Havenar-Daughton,et al.  Cutting Edge: The Direct Action of Type I IFN on CD4 T Cells Is Critical for Sustaining Clonal Expansion in Response to a Viral but Not a Bacterial Infection1 , 2006, The Journal of Immunology.

[13]  S. Akira,et al.  Pathogen Recognition and Innate Immunity , 2006, Cell.

[14]  G. Kochs,et al.  The interferon response circuit: Induction and suppression by pathogenic viruses , 2005, Virology.

[15]  J. Sprent,et al.  Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection , 2005, The Journal of experimental medicine.

[16]  Osamu Takeuchi,et al.  Cell type-specific involvement of RIG-I in antiviral response. , 2005, Immunity.

[17]  D. Levy,et al.  Tissue-specific Positive Feedback Requirements for Production of Type I Interferon following Virus Infection* , 2005, Journal of Biological Chemistry.

[18]  D. Golenbock,et al.  MyD88 is critical for the development of innate and adaptive immunity during acute lymphocytic choriomeningitis virus infection , 2005, European journal of immunology.

[19]  P. Borrow,et al.  Rapid Activation of Spleen Dendritic Cell Subsets following Lymphocytic Choriomeningitis Virus Infection of Mice: Analysis of the Involvement of Type 1 IFN1 , 2005, The Journal of Immunology.

[20]  E. Zúñiga,et al.  Viruses evade the immune system through type I interferon-mediated STAT2-dependent, but STAT1-independent, signaling. , 2005, Immunity.

[21]  S. Gloster,et al.  Virus infection‐associated bone marrow B cell depletion and impairment of humoral immunity to heterologous infection mediated by TNF‐α/LTα , 2005, European journal of immunology.

[22]  G. Kochs,et al.  Inverse interference: how viruses fight the interferon system. , 2004, Viral immunology.

[23]  C. Horvath.  Weapons of STAT destruction , 2004 .

[24]  Jose L Pruneda-Paz,et al.  Bone marrow plasmacytoid dendritic cells can differentiate into myeloid dendritic cells upon virus infection , 2004, Nature Immunology.

[25]  Shizuo Akira,et al.  The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses , 2004, Nature Immunology.

[26]  Shizuo Akira,et al.  Innate Antiviral Responses by Means of TLR7-Mediated Recognition of Single-Stranded RNA , 2004, Science.

[27]  R. Brutkiewicz,et al.  Myeloid marker expression on antiviral CD8+ T cells following an acute virus infection , 2003, European journal of immunology.

[28]  D. Levy,et al.  Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock , 2003, Nature Immunology.

[29]  D. Besselsen,et al.  Detection of sendai virus and pneumonia virus of mice by use of fluorogenic nuclease reverse transcriptase polymerase chain reaction analysis. , 2003, Comparative medicine.

[30]  M. Capobianchi,et al.  HCV and interferon: viral strategies for evading innate defence mechanisms in the virus-host battle , 2003, Cell Death and Differentiation.

[31]  S. Akira,et al.  Recognition of pathogen-associated molecular patterns by TLR family. , 2003, Immunology letters.

[32]  Tomoki Ito,et al.  Roles of toll-like receptors in natural interferon-producing cells as sensors in immune surveillance. , 2002, Human immunology.

[33]  Christine A. Biron,et al.  Coordinated and Distinct Roles for IFN-αβ, IL-12, and IL-15 Regulation of NK Cell Responses to Viral Infection1 , 2002, The Journal of Immunology.

[34]  R. Salomon,et al.  Critical Role for STAT4 Activation by Type 1 Interferons in the Interferon-γ Response to Viral Infection , 2002, Science.

[35]  Michael G. Katze,et al.  Viruses and interferon: a fight for supremacy , 2002, Nature Reviews Immunology.

[36]  D. Tough,et al.  Links between innate and adaptive immunity via type I interferon. , 2002, Current opinion in immunology.

[37]  C. Biron,et al.  Promotion of Alpha/Beta Interferon Induction during In Vivo Viral Infection through Alpha/Beta Interferon Receptor/STAT1 System-Dependent and -Independent Pathways , 2002, Journal of Virology.

[38]  G. Trinchieri,et al.  Interferon (cid:2) / (cid:3) and Interleukin 12 Responses to Viral Infections: Pathways Regulating Dendritic Cell Cytokine Expression In Vivo , 2002 .

[39]  Marc Dalod,et al.  Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology , 2001, Nature Immunology.

[40]  D. Moskophidis,et al.  Critical Role for Alpha/Beta and Gamma Interferons in Persistence of Lymphocytic Choriomeningitis Virus by Clonal Exhaustion of Cytotoxic T Cells , 2001, Journal of Virology.

[41]  G. Schuler,et al.  Culture of bone marrow cells in GM‐CSF plus high doses of lipopolysaccharide generates exclusively immature dendritic cells which induce alloantigen‐ specific CD4 T cell anergy in vitro , 2000, European journal of immunology.

[42]  N. Kadowaki,et al.  The nature of the principal type 1 interferon-producing cells in human blood. , 1999, Science.

[43]  D. Levy,et al.  Differential viral induction of distinct interferon‐α genes by positive feedback through interferon regulatory factor‐7 , 1998, The EMBO journal.

[44]  R. Zinkernagel,et al.  Virus-induced Transient Bone Marrow Aplasia: Major Role of Interferon-α/β during Acute Infection with the Noncytopathic Lymphocytic Choriomeningitis Virus , 1997, The Journal of experimental medicine.

[45]  P. Ricciardi-Castagnoli,et al.  Establishment of a cell line with features of early dendritic cell precursors from fetal mouse skin , 1995, European journal of immunology.

[46]  R. Zinkernagel,et al.  Antiviral defense in mice lacking both alpha/beta and gamma interferon receptors , 1995, Journal of virology.

[47]  R. Zinkernagel,et al.  Antiviral protection by vesicular stomatitis virus-specific antibodies in alpha/beta interferon receptor-deficient mice , 1995, Journal of virology.

[48]  P. Borrow,et al.  Virus-induced immunosuppression: immune system-mediated destruction of virus-infected dendritic cells results in generalized immune suppression , 1995, Journal of virology.

[49]  M Aguet,et al.  Functional role of type I and type II interferons in antiviral defense. , 1994, Science.

[50]  R. Zinkernagel,et al.  Resistance of lymphocytic choriomeningitis virus to alpha/beta interferon and to gamma interferon , 1994, Journal of virology.

[51]  P. Borrow,et al.  Virus-induced immunosuppression. 1. Age at infection relates to a selective or generalized defect. , 1993, Virology.

[52]  Li Wu,et al.  The surface phenotype of dendritic cells purified from mouse thymus and spleen: investigation of the CD8 expression by a subpopulation of dendritic cells , 1992, The Journal of experimental medicine.

[53]  R. Zinkernagel,et al.  Virus-triggered acquired immunodeficiency by cytotoxic T-cell-dependent destruction of antigen-presenting cells and lymph follicle structure. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[54]  O. Strannegard,et al.  Interferon-alpha and tumor necrosis factor-alpha in serum of patients in various stages of HIV-1 infection. , 1991, AIDS research and human retroviruses.

[55]  R. Ahmed,et al.  Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence , 1984, The Journal of experimental medicine.

[56]  C. Biron,et al.  Elevated natural killer cell-mediated cytotoxicity, plasma interferon, and tumor cell rejection in mice persistently infected with lymphocytic choriomeningitis virus. , 1983, Journal of immunology.

[57]  M. Oldstone,et al.  Genomic and biological variation among commonly used lymphocytic choriomeningitis virus strains. , 1983, The Journal of general virology.

[58]  M. Saron,et al.  Chronic production of interferon in carrier mice congenitally infected with lymphocytic choriomeningitis virus. , 1982, Virology.

[59]  R. Friedman,et al.  Interferon induction by lymphocytic choriomeningitis viruses correlates with maximum virulence. , 1981, The Journal of general virology.

[60]  T. Merigan,et al.  Interferon production during lymphocytic choriomeningitis virus infection of nude and normal mice , 1977, Nature.

[61]  I. Gresser,et al.  A Method for the Large Scale Production of Potent Interferon Preparations , 1974, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[62]  E. A. Havell,et al.  Reduced interferon response in mice congenitally infected with lymphocytic choriomeningitis virus. , 1970, The Journal of general virology.

[63]  K. Cassady.  Lymphocytic Choriomeningitis Virus , 2006 .

[64]  L. Martínez Peralta,et al.  Lymphocytic choriomeningitis virus , 2005, Archives of Virology.

[65]  C. Horvath.  Weapons of STAT destruction. Interferon evasion by paramyxovirus V protein. , 2004, European journal of biochemistry.

[66]  D. Leib.  Counteraction of interferon-induced antiviral responses by herpes simplex viruses. , 2002, Current topics in microbiology and immunology.

[67]  M. Brunda,et al.  Interferons and Other Cytokines , 1997 .

[68]  K. Bro-Jørgensen.  The interplay between lymphocytic choriomeningitis virus, immune function, and hemopoiesis in mice. , 1978, Advances in virus research.

[69]  K. Bro-Jørgensen,et al.  Changes in hemopoiesis during the course of acute LCM virus infection in mice. , 1977, Blood.