CHARACTERIZING DSRNA-INDUCED IMMUNE RESPONSES DURING SEASONAL HUMAN ALPHACORONAVIRUS INFECTION
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Abstract
Coronaviruses (CoVs) are positive-sense single-stranded RNA viruses that can cause diseases in mammals. Despite detectable double-stranded (ds)RNA production during infection, CoVs are adept at evading or suppressing the activation of host innate immune responses during infection. We optimized culturing techniques for human alphacoronaviruses (229E and NL63) and established a primary nasal epithelial culture model to study how the human alphacoronaviruses evade the dsRNA-induced innate immune pathways, including type I and III interferon (IFN) production and signaling, protein kinase R (PKR), and oligoadenylate synthetase ribonuclease L (OAS/RNase L). We found that human alphacoronaviruses do not evade the IFN and PKR pathways. During infection with 229E encoding a catalytically inactive conserved endoribonuclease (EndoU) domain, we demonstrate that EndoU plays a role in how human alphacoronaviruses antagonize the dsRNA-induced antiviral pathways. Furthermore, we examined the role of temperature on HCoV infections. We found that temperature modulates human alpha- and betacoronavirus replication in nasal epithelial cultures. We also investigated the IFN sensitivity of human coronaviruses and found that inhibition of IFN signaling leads to delayed clearance of human alpha- but not betacoronaviruses. We also observed that host IFN responses are regulated by temperature, with increased viral clearance at warmer temperatures during human coronavirus infection. Overall, we found that the interactions between the human alphacoronaviruses and dsRNA-induce innate immunity differentiate them from the highly lethal and pathogenic human betacoronaviruses. Our findings fill gaps in the knowledge of how human alphacoronaviruses interact with the innate immune system.