Omicron‐induced interferon signaling prevents influenza A H1N1 and H5N1 virus infection

Abstract

Recent findings in permanent cell lines suggested that SARS-CoV-2 Omicron BA.1 induces a stronger interferon response than Delta. Here, we show that BA.1 and BA.5 but not Delta induce an antiviral state in air-liquid interface cultures of primary human bronchial epithelial cells and primary human monocytes. Both Omicron subvariants caused the production of biologically active types I (α/β) and III (λ) interferons and protected cells from super-infection with influenza A viruses.Notably, abortive Omicron infection of monocytes was sufficient to protect monocytes from influenza A virus infection. Interestingly, while influenza-like illnesses surged during the Delta wave in England, their spread rapidly declined upon the emergence of Omicron. Mechanistically, Omicron-induced interferon signaling was mediated via double-stranded RNA recognition by MDA5, as MDA5 knockout prevented it. The JAK/STAT inhibitor baricitinib inhibited the Omicron-mediated antiviral response, suggesting it is caused by MDA5-mediated interferon production, which activates interferon receptors that then trigger JAK/STAT signaling. In conclusion, our study (1) demonstrates that only Omicron but not Delta induces a substantial interferon response in physiologically relevant models, (2) shows that

RNA editing in host lncRNAs as potential modulator in SARS-CoV-2 variants-host immune response dynamics

“…The increased interferon response in Omicron patients has been reported in a few other studies as well. 38 , 39 , 40 Consequently, the interferon stimulated gene (ISG) expression was also higher in the Omicron infected patients. Among the ISGs, the RNA editing related genes of ADAR and APOBEC3 families were significantly upregulated in the Omicron but downregulated in the Delta, compared to the PreVOC group ( Figure 2 A).…”