Lethal viral infection results from STAT1 but not STAT2 or IRF9 deficiency in mice and is mediated by CD4+ T-cells (44.11)

Abstract

Abstract Type I IFN (α/β) signaling is crucial in the antiviral response and is mediated by STAT1, STAT2 and IRF9 while type II IFN (γ) uses STAT1. We studied the role of STAT1, STAT2 and IRF9 in the host response to systemic infection with lymphocytic choriomeningitis virus (LCMV). In wild type (WT), STAT2 KO and IRF9 KO mice, infection was non-lethal and virus was either cleared (WT) or established persistence (STAT2 and IRF9 KO). In contrast, in STAT1 KO mice, infection was lethal with severe immune pathology with T-cells, macrophages and granulocytes and elevated expression of various cytokines, particularly IFN-γ, present in various organs. However, lethality was unaltered in LCMV-infected STAT1 KO mice that lacked the IFN-γ receptor. While clearance of LCMV in WT mice is mediated by CD8+ T-cells, depletion of these cells in LCMV-infected STAT1 KO mice did not affect lethality. However, depletion of CD4+ T-cells prevented lethality in LCMV-infected STAT1 KO mice with a considerable reduction in tissue immune pathology. In vitro stimulation assays revealed a skewing of the T-cell response to the Th17 phenotype in LCMV-infected STAT1 KO but not WT mice. These findings indicated that STAT1 has a major protective function in LCMV infection, not only being crucial for limiting viral replication and spread, but also preventing the emergence of a lethal CD4+ T-cell response possibly mediated by Th17 cells. Support : NHMRC grant 512407.