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bioRxiv · 10.1101/702837

Rotavirus infection induces both interferon (IFN) and inflammatory resistance by re-programming intestinal IFN receptor signaling

Sen, A.·Namsa, N.·Feng, N.·Greenberg, H. B.
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Abstract

Rotaviruses (RV) cause acute severe diarrhea in the absence of substantial intestinal inflammation. They are also highly infectious in their homologous host species. The efficient replication capacity of RV in the small bowel is substantially linked to its ability to inhibit different types of interferons (IFNs). Here, we find that during RV infection in vitro, both virus-infected and uninfected bystander cells resist STAT1 phosphorylation and IRF7 induction in response to exogenous IFN. Functionally, cellular transcription in response to exogenous stimulation with IFN, but not intracellular dsRNA, was inhibited by RV. Further, IFNAR1 stimulation during RV infection significantly repressed a set of virus-induced transcripts. Regulation of IFN signaling in vivo was studied in suckling mice using the highly infectious homologous murine EW RV strain. Kinetic studies indicated that whereas sustained EW RV replication and IFN induction occurred in the small intestine, IFN-stimulated transcripts significantly decreased over time. In addition, LPS-mediated intestinal damage, driven by STAT1-induced inflammation, was prevented in EW RV-infected mice. Remarkably, ectopic stimulation of either IFNAR1 or IFNGR1 in murine RV-infected mice eliminated several intestinal antiviral and inflammatory transcriptional responses to RV. In contrast to homologous murine RV, infection with a STAT1-sensitive heterologous simian RV strain induced multiple IFN-stimulated transcripts, inflammatory cytokines, and intestinal expression of STAT1-pY701. Finally, RV strain-specific STAT1 regulation in the gut plays a prominent role in the activation of multiple intestinal caspases. On the other hand, the simian RRV strain, but not murine EW RV, uniquely triggers the cleavage of both extrinsic and intrinsic caspases (-8, -9, and -3) in a STAT1-mediated manner. Collectively, these findings reveal efficient re-programing of multiple IFN receptors in the gut towards a negative feedback mode of signaling, accompanied by suppression of IFN-mediated antiviral, apoptotic, and inflammatory functions, during natural RV intestinal infection.

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Sen, A., Namsa, N., Feng, N., Greenberg, H. B.. 2019-07-15. Rotavirus infection induces both interferon (IFN) and inflammatory resistance by re-programming intestinal IFN receptor signaling. https://doi.org/10.1101/702837

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