Interferon gamma modulation of disease manifestation and the local antibody response to alphavirus encephalomyelitis.
Infection of mice with Sindbis virus (SINV) produces encephalomyelitis and provides a model for examination of the central nervous system (CNS) immune response to alphavirus infection. Clearance of infectious virus is accomplished through a cooperative effort between SINV-specific antibody and IFN-γ, but the regulatory interactions are poorly understood. To determine the effects of IFN-γ on clinical disease and the antiviral immune response, C57BL/6 mice lacking IFN-γ (Ifng-/-) or IFN-γ receptor (Ifngr1-/-) were studied in comparison to WT mice. Maximum production of Ifng mRNA and IFN-γ protein in the CNS of WT and Ifngr1-/- mice occurred 5-7 days after infection, with higher levels of IFN-γ in Ifngr1-/- mice. Onset of clinical disease was earlier in mice with impaired IFN-γ signalling, although Ifngr1-/- mice recovered more rapidly. Ifng-/- and Ifngr1-/- mice maintained body weight better than WT mice, associated with better food intake and lower brain levels of inflammatory cytokines. Clearance of infectious virus from the spinal cords was slower, and CNS, but not serum, levels of SINV-specific IgM, IgG2a and IgG2b were lower in Ifngr1-/- and Ifng-/- mice compared to WT mice. Decreased CNS antiviral antibody was associated with lower expression of mRNAs for B-cell attracting chemokines CXCL9, CXCL10 and CXCL13 and fewer B cells in the CNS. Therefore, IFN-γ signalling increases levels of CNS pro-inflammatory cytokines, leading to clinical disease, but synergistically clears virus with SINV-specific antibody at least in part by increasing chemokine production important for infiltration of antibody-secreting B cells into the CNS.
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.|Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Victoria K
VK
Baxter
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Diane E
DE
Griffin
D018354:Alphavirus Infections / Q000276:immunology* / Q000821:virology; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology; D002490:Central Nervous System / Q000276:immunology / Q000821:virology; D016207:Cytokines / Q000276:immunology; D004679:Encephalomyelitis / Q000276:immunology* / Q000821:virology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012845:Sindbis Virus / Q000276:immunology* / Q000502:physiology
D000914:Antibodies, Viral; D016207:Cytokines; D007371:Interferon-gamma
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