Compromised virus control and augmented perforin-mediated immunopathology in IFN-gamma-deficient mice infected with lymphocytic choriomeningitis virus

To define tbe role of IFN-gamma in the control of acute infection with a no ncytopathogenic virus, mice with targeted defects of the genes encoding IFN -gamma, perforin, or both were infected i,v, with Cove strains of lymphocyt ic choriomeningitis virus differing markedly in their capacity to spread in wild-type mice, Our results reveal that IFN-gamma is pivotal to T cell-med iated control of a rapidly invasive stain, whereas it is less important in the acute elimination of a slowly invasive strain. Moreover, the majority o f mice infected with the rapidly invasive strain succumb to a wasting syndr ome mediated by CD8(+) effector cells, The primary effector mechanism under lying this disease is perforin-dependent lysis, but other mechanisms are al so involved, Wasting disease can be prevented if naive CD8+ cells from mice transgenic for an MHC class I-restricted lymphocytic choriomeningitis viru s-specific TCR are adoptively transferred before virus challenge, indicatin g that the disease is the result of an unfortunate balance between virus re plication in internal organs, e,g,, liver and spleen, and the host response ; resetting this balance by increasing host responsiveness will again had t o a rapidly controlled infection and limited tissue damage. Thus, the prese nce or absence of IFN-gamma determines whether CTLs will clear infection wi th this noncytopathogenic virus or induce severe immunopathology.