Abstract
We have shown that following systemic infection with lymphocytic choriomeningitis virus (LCMV), STAT1 KO but not WT, IFNAR KO, STAT1/IFNAR DKO, STAT2 KO or STAT1/STAT2 DKO mice develop type I-IFN-dependent, CD4+ T-cell-mediated lethal disease. Here we determined the underlying molecular mechanisms of this disease. Following infection, higher levels of LCMV were observed in peripheral organs of all the KO genotypes compared with the WT mice. However, IFN- β levels were significantly higher in the serum of LCMV-infected STAT1 and IFNAR KO mice compared with WT, STAT1/IFNAR and STAT1/STAT2 DKO mice. IFN- γ levels were similar between all genotypes of mice. Moreover, STAT1 phosphorylation was induced in peripheral organs of LCMV-infected WT and IFNAR KO mice, while STAT2 phosphorylation was induced in STAT1 KO mice, but not in WT, IFNAR KO or STAT1/IFNAR DKO mice. LCMV-infected STAT1 KO mice had higher STAT3 phosphorylation than WT and STAT1/IFNAR DKO mice. During infection, SOCS1 mRNA was induced in STAT1 KO mice and in WT, IFNAR and STAT2 KO mice with differing kinetics but was not induced in STAT1/IFNAR and STAT1/STAT2 DKO mice. However, SOCS3 mRNA was induced to similar levels and kinetics in all genotypes of mice during infection. We conclude that STAT1-independent, STAT2-dependent non-canonical IFN-I signaling during LCMV infection: (1) was insufficient to limit viral replication and spread, (2) positively regulated the production of IFN- β , (3) resulted in activation of downstream signaling molecules, STAT2 and STAT3, and (4) induced the negative regulator of IFN signaling, SOCS1.
Published Version
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