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PloS One


Pivotal components of the IFN response to virus infection include the IFN receptors (IFNR), and the downstream factorsignal transducer and activator of transcription 1 (Stat1). Mice deficient for Stat1 and IFNR (Stat12/2 and IFNaßcR2/2 mice) lack responsiveness to IFN and exhibit high sensitivity to various pathogens. Here we examined herpes simplex virus type 1 (HSV-1) pathogenesis in Stat12/2 mice and in IFNaßcR2/2 mice following corneal infection and bioluminescent imaging. Two divergent and paradoxical patterns of infection were observed. Mice with an N-terminal deletion in Stat1 (129Stat12/2(N-term)) had transient infection of the liver and spleen, but succumbed to encephalitis by day 10 post-infection. In stark contrast, infection of IFNaßcR2/2 mice was rapidly fatal, with associated viremia and fulminant infection of the liver and spleen, with infected infiltrating cells being primarily of the monocyte/macrophage lineage. To resolve the surprising difference between Stat12/2 and IFNaßcR2/2 mice, we infected an additional Stat12/2 strain deleted in the DNA-binding domain (129Stat12/2 (DBD)). These 129Stat12/2 (DBD) mice recapitulated the lethal pattern of liver and spleen infection seen following infection of IFNaßcR2/2 mice. This lethal pattern was also observed when 129Stat12/2 (N-term) mice were infected and treated with a Type I IFN-blocking antibody, and immune cells derived from 129Stat12/2 (N-term) mice were shown to be responsive to Type I IFN. These data therefore show significant differences in viral pathogenesis between two commonly-used Stat12/2 mouse strains. The data are consistent with the hypothesis that Stat12/2 (N-term) mice have residual Type I IFN receptor-dependent IFN responses. Complete loss of IFN signaling pathways allows viremia and rapid viral spread with a fatal infection of the liver. This study underscores the importance of careful comparisons between knockout mouse strains in viral pathogenesis, and may also be relevant to the causation of HSV hepatitis in humans, a rare but frequently fatal infection.