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David A. Leib, David R. Piwnica-Worms, Megan A. O'Connor, Lynne Collins, TracyJo Pasieka; Bioluminescent Imaging of Herpes Simplex Virus Corneal Infection of Stat1-Deficient Mice Reveals Resistance Through a Residual Type-1 Interferon Response. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1209.
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© ARVO (1962-2015); The Authors (2016-present)
To determine the roles of innate signaling components (in particular, interferon receptors and Stat1) in determining the tropism, spread and virulence of herpes simplex virus following corneal infection.
Mice deficient for interferon (IFN) receptors and Stat1 were corneally infected with HSV-1 strain KOSdlux, a virus engineered to express high levels of luciferase. Mice were examined daily using bioluminescence imaging (BLI), as well as for disease and pathology. In addition, mice were sampled in order to assess viral titers, and for expression of cytokines in serum.
Dramatic differences in lethality, disease, and tropism following corneal inoculation with herpes simplex virus type 1 (HSV-1) were noted in Stat1-/- and IFNαβγR-/- mice relative to each other, and compared to control mice. Bioluminescent imaging (BLI) revealed that the strain 129 Stat1-/- mice controlled a disseminated visceral infection of the liver and spleen, but subsequently succumbed to CNS infection by day 10 postinfection. In contrast, strain IFNαβγR-/- mice were unable to control visceral infection and succumbed quickly to infection with high viral loads in multiple tissues within 5 days. Moreover, infected 129 Stat1-/- mice produced Type I IFN, and primary cells derived from these mice responded to exogenous Type I IFN. Strain 129 Stat1-/- mice treated with a type I IFN-blocking antibody died rapidly with a pattern strongly resembling that seen in the IFNαβγR-/- mice. This provided further evidence for an IFN receptor-dependent response in the strain 129 Stat1-/- mice. Studies in C57Bl6 Stat1-/- mice revealed strong similarities to the IFNαβγR-/- mice suggesting fundamental differences between the 129 and C57Bl6 Stat-deficient strains.
These studies therefore reveal low, but residual Type I IFN receptor-dependent IFN responses in the 129 Stat1-/- mice that are capable of clearing peripheral, but not CNS infection. These studies demonstrate the potency of even a weakened IFN response in controlling virus infection, and highlight surprising and critical differences in mice lacking various components of the IFN signaling pathway.
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