The T-cell-independent role of gamma interferon and tumor necrosis factor alpha in macrophage activation during murine cytomegalovirus and herpes simplex virus infections.
We defined the normal and innate (without functional B or T cells) inflammatory response to infection with mouse cytomegalovirus (MCMV) or herpes simplex virus (HSV). Intraperitoneal infection with MCMV or HSV induced an inflammatory infiltrate consisting largely of macrophages (M phi) in both normal CB17 and severe combined immunodeficient (SCID) mice (lacking functional B or T cells). M phi from infected mice were activated as shown by (i) spread morphology, (ii) increased expression of major histocompatibility complex (MHC) class II, MHC class I, and intercellular adhesion molecule-1 molecules, and (iii) downregulation of M phi-specific cell surface protein F4/80. In vivo administration of neutralizing antibodies specific for gamma interferon (IFN gamma) or tumor necrosis factor alpha (TNF alpha) inhibited MHC class II induction on infiltrating M phi in both normal and CB17 SCID mice. Anti-TNF alpha decreased the number of M phi in virus-induced inflammatory exudates. The MCMV titer increased in the spleen and liver of IFN gamma-depleted SCID mice, while TNF alpha depletion increased only splenic titers. MCMV-induced pathology was also increased in spleens of IFN gamma- and TNF alpha-depleted SCID mice. We conclude that (i) M phi activation is a prominent part of inflammatory responses to herpesvirus infection and (ii) IFN gamma and TNF alpha play a critical role in both virus-induced M phi activation and control of herpesvirus growth independent of T and B cells. This suggests that IFN gamma- and TNF alpha-mediated M phi activation is an important aspect of innate immunity to viral infection. As the M phi may be involved in MCMV latency, IFN gamma- and TNF alpha-dependent M phi activation during primary infection may be relevant to establishment of viral latency.
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Center for Immunology, Washington University School of Medicine, St. Louis, Missouri 63110.
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D000818:Animals; D006224:Cricetinae; D003586:Cytomegalovirus Infections / Q000276:immunology*; D006561:Herpes Simplex / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D007371:Interferon-gamma / Q000502:physiology*; D008262:Macrophage Activation; D051379:Mice; D016513:Mice, SCID; D051381:Rats; D013601:T-Lymphocytes / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D000949:Histocompatibility Antigens Class II; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma