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) inf lammatory response to infection with mouse cytomegalovirus (MCMV) or h erpes 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 o f neutralizing antibodies specific for gamma interferon (IFN gamma) or tumor necrosis factor alpha (TNF alpha) inhibited MHC class II induct ion on infiltrating M phi in both normal and CB17 SCID mice. Anti-TNF alpha decreased the number of M phi in virus-induced inflammatory exud ates, The MCMV titer increased in the spleen and liver of IFN gamma-de pleted SCID mice, while TNF alpha depletion increased only splenic tit ers, MCMV-induced pathology was also increased in spleens of IFN gamma - and TNF alpha-depleted SCID mice. We conclude that (i) M phi activat ion is a prominent part of inflammatory responses to herpesvirus infec tion and (ii) IFN gamma and TNF alpha play a critical role in both vir us-induced M phi activation and control of herpesvirus growth independ ent of T and B cells. This suggests that IFN gamma- and TNF alpha-medi ated M phi activation is an important aspect of innate immunity to vir al 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.