32: IRF7-dependent, type I IFN (IFN-I) production induces lethal immune-mediated disease in STAT1 KO mice infected with LCMV

Abstract

STAT1 KO but not WT, STAT2 KO, IRF9 KO or IFNAR KO mice succumb to a lethal CD4+ T cell-mediated disease following systemic infection with lymphocytic choriomeningitis virus (LCMV). In previous studies we showed: (i) LCMV infection induces IRF7 gene expression in a STAT1-independent, but STAT2-dependent manner, and (2) IRF7 is required for IFN-alpha but not IFN-βeτα production in LCMV infection. Here we examined the role of IRF7 in the lethal host response to LCMV infection in STAT1 KO mice. In contrast to STAT1 KO mice, STAT1/IRF7 double KO mice survived LCMV infection and had a marked reduction in immune pathology affecting key organs including the liver, kidney and lung. LCMV infection in STAT1 KO mice was associated with a significant elevation of a number of cytokines in the serum including IFN-αλπηα, IFN-βeτα, IFN-γαμμα, IL-5, IL-6 and MCP1 but this response was absent in STAT1/IRF7 KO mice which had a modest increase in MCP-1 only. In addition, in the spleen of LCMV-infected STAT1 KO mice, IFN-βeτα and IFN-γαμμα mRNAs were also much more highly induced when compared with WT mice, while in STAT1/IRF7 KO mice IFN-γαμμα mRNA induction was similar to WT animals, there was no induction of IFN-βeτα mRNA. To elucidate further a possible role of IFN-I in lethal disease, we examined STAT1/IFNAR double KO mice. In contrast to STAT1 KO mice that all succumbed to lethal disease, STAT1/IFNAR KO mice all survived infection with LCMV. In conclusion, lethality resulting from LCMV infection in STAT1 KO mice requires IRF7-dependent, IFN-I production which drives a catastrophic antiviral immune response.