RT Journal Article
SR Electronic
T1 Rotavirus infection induces both interferon (IFN) and inflammatory resistance by re-programming intestinal IFN receptor signaling
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 702837
DO 10.1101/702837
A1 Adrish Sen
A1 Nima D. Namsa
A1 Ningguo Feng
A1 Harry B. Greenberg
YR 2019
UL http://biorxiv.org/content/early/2019/07/15/702837.abstract
AB Rotaviruses (RV) cause acute severe diarrhea and are highly infectious in homologous host species. However, RV infection does not cause appreciable intestinal inflammation and homologous RV replication resists the antiviral effects of different interferon (IFN) types. In suckling mice, we found that homologous murine EW RV triggers sustained induction of IFNs, but not the amplification of interferon-stimulated genes (ISGs) or inflammatory transcripts. IFNs can trigger both apoptosis and inflammatory necroptotic cell death pathways. However, during RV infection intestinal epithelial cells (IECs) are severely impaired in the cleavage of different caspases regulating intrinsic and extrinsic cell death. Inhibition of caspase cleavage occurs in both RV-infected and -uninfected bystander IECs. In contrast, RV induces cleavage of receptor-interacting protein 1 (RIP1), a master regulator of cell death and survival decisions. Comparison of IFN-resistant (homologous) and -sensitive (heterologous) RV strains in mice demonstrates that successful RV infection restricts IFN receptor (IFNR)-amplified intestinal inflammatory cytokine secretion. LPS-mediated intestinal damage, driven by IFNR-induced inflammatory necroptosis, is also prevented during ongoing homologous RV infection. We find that the ability of RV to negate IFNR-mediated antiviral and inflammatory functions may involve a two-pronged attack. First, RV infection induces resistance to IFNAR1-directed STAT1 activation in bystander cells and inhibits IFNR-feedforward amplification. Second, ectopic stimulation of different IFNRs during RV infection results in efficient negative feedback transcription, eliminating several host innate responses to infection. Our study reveals a novel mechanism underlying the ability of homologous RV to dismantle the antiviral and inflammatory arms of several intestinal IFN types.Significance Interferons mediate distinct functions including amplification of antiviral and inflammatory genes and inflammatory necroptosis of cells. Here we show that rotavirus (RV) infection of small intestinal epithelial cells (IECs) subverts IFNR-mediated antiviral and inflammatory functions. Although RV sensitizes both infected and uninfected bystander IECs to acute necroptosis, it prevents intestinal inflammation and induces cleavage of a key necroptosis regulator, RIP1K. During RV infection, uninfected bystander cells resist IFN-mediated STAT1 phosphorylation and feedforward transcription is blocked. In addition, ectopic stimulation of IFNRs during RV infection triggers negative-feedback signaling and eliminates several host antiviral and inflammatory responses. Thus, perturbation of IFNR feedback, recently linked to IFN resistance in cancer and inflammatory pathologies, is also exploited by an acute viral pathogen, RV.