Omicron-induced interferon signalling prevents influenza A H1N1 and H5N1 virus infection

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 (ALI) cultures of primary human bronchial epithelial (HBE) cells and primary human monocytes. Both Omicron subvariants caused the production of biologically active type 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 signalling was mediated via double-stranded RNA recognition by MDA5, as MDA5 knock-out 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 signalling. In conclusion, our study 1) demonstrates that only Omicron but not Delta induces a substantial interferon response in physiologically relevant models, 2) shows that Omicron infection protects cells from influenza A virus super-infection, and 3) indicates that BA.1 and BA.5 induce comparable antiviral states. 

 

Comments：

It seems that recent research has found that SARS-CoV-2 Omicron BA.1 and BA.5 subvariants, but not Delta, induce a strong interferon response in air-liquid interface (ALI) cultures of primary human bronchial epithelial (HBE) cells and primary human monocytes. The interferon response was mediated via double-stranded RNA recognition by MDA5 and involved the production of biologically active type I (α/β) and III (λ) interferons. This interferon response was able to protect cells from super-infection with influenza A viruses. Interestingly, Omicron-induced interferon signaling was found to be responsible for the decline of influenza-like illnesses upon the emergence of Omicron in England. The study also suggests that BA.1 and BA.5 induce comparable antiviral states. Finally, the JAK/STAT inhibitor baricitinib was found to inhibit the Omicron-mediated antiviral response, suggesting that the response is caused by MDA5-mediated interferon production that activates interferon receptors, which then trigger JAK/STAT signaling.

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S2851	Baricitinib	Baricitinib is a selective JAK1 and JAK2 inhibitor with IC50 of 5.9 nM and 5.7 nM in cell-free assays, ~70 and ~10-fold selective versus JAK3 and Tyk2, no inhibition to c-Met and Chk2. Baricitinib is found to reduce or interrupt the passage of the virus into target cells and is used in the treatment research for COVID-19. Phase 3.

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