3 years ago

Rotavirus degrades multiple type interferon receptors to inhibit IFN signaling and protects against mortality from endotoxin in suckling mice.

Harry B Greenberg, Ayushi Sharma, Adrish Sen
STAT1 phosphorylation in response to exogenous IFN administration can be inhibited by rotaviral replication both in vitro and in vivo. In addition many rotavirus strains are resistant to the actions of different IFN types . The regulation of multiple IFN type-mediated antiviral pathways by RVs is not well understood. In this study, we find that during infection in vitro and in vivo RV significantly depletes IFN-type I, II, and III receptors (IFNRs). Regulation of IFNRs occurred exclusively within RV-infected cells and could be abrogated by inhibiting the lysosomal-endosomal degradation pathway. In vitro, IFNR degradation was conserved across multiple RV strains that differ in their modes of regulating IFN induction. In suckling mice, exogenously administered types I, II, or III IFN each induced phosphorylation of STAT1-Y701 within intestinal epithelial cells (IECs) of suckling mice. Murine EW strain RV infection transiently activated intestinal STAT1 at 1dpi, but not subsequently at 2-3dpi. In response to injection of purified IFN-α/β or -λ, IECs in EW-infected mice exhibited impaired STAT1-Y701 phosphorylation, correlating with depletion of different intestinal IFNRs and impaired IFN-mediated transcription. The ability of EW murine RV to inhibit multiple IFN types led us to test protection of suckling mice from endotoxin-mediated shock, an outcome that is dependent on the host IFN response. Compared to controls, mice infected with EW murine RV were substantially protected against mortality following parenteral endotoxin administration. These studies identify a novel mechanism of IFN subversion by RV and reveal an unexpected protective effect of RV infection on endotoxin-mediated shock in suckling mice.IMPORTANCE Antiviral functions of types 1, 2, and 3 IFN are mediated by receptor-dependent activation of STAT1. Here we find that RV degrades the types 1, 2, and 3 IFN receptors (IFNR) in vitro In a suckling mouse model, RV effectively blocked STAT1 activation and transcription following injection of different purified IFNs. This correlated with significantly decreased protein expression of intestinal types 1 and 2 IFNRs. Recent studies demonstrate that in mice, LPS-induced lethality is prevented by genetic ablation of IFN signaling genes such as IFNAR1 and STAT1. When suckling mice were infected with RV they were substantially protected from lethal exposure to endotoxin. These findings provide novel insights into the mechanisms underlying rotavirus regulation of different interferons and are likely to stimulate new research into both rotavirus pathogenesis and endotoxemia.

Publisher URL: http://doi.org/10.1128/JVI.01394-17

DOI: 10.1128/JVI.01394-17

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