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Review 1: "Omicron-induced interferon signalling prevents influenza A virus infection"

The authors demonstrate differential interferon-signaling in SARS-CoV-2 Delta and Omicron variants, which is correlated with the ability of Omicron infection, but not Delta infection, to protect in vitro cell cultures from subsequent influenza A virus co-infection.

Published onOct 30, 2022
Review 1: "Omicron-induced interferon signalling prevents influenza A virus infection"
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Omicron-induced interferon signalling prevents influenza A virus infection
Description

AbstractRecent 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.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review:

In this study, the authors demonstrated that infection of human primary cell cultures with the SARS-CoV-2 Omicron variant induced a significant amount of biologically active type I and type III interferon, while infection with the Delta variant did not induce interferon responses. This correlated with the ability of SARS-CoV-2 Omicron infection, but not Delta infection, to protect the cell cultures from subsequent influenza A virus co-infection. The study design, methodology, and data analysis were all performed in a scientifically sound manner and the results are convincing.

An important point is that the study was conducted using human primary cell cultures, which increases its clinical relevance. Also, the authors indicate in Supplementary Figure 3 that in the human population, when Delta was the primary circulating SARS-CoV-2 variant of concern, influenza cases surged after restrictions were lifted, while after the Omicron variant became prevalent, the number of influenza-like illnesses strongly declined. These facts further increase the manuscript’s clinical relevance. However, all experiments were conducted using only an in vitro cell culture system and there were no in vivo animal studies to validate the findings. This is a major limitation of the study, which, to their credit, the authors clearly acknowledge in the Discussion.

In the whole animal, it is possible that other cytokines could be differentially induced by Delta versus Omicron infection, and at various times after infection, such that these additional cytokines could impact susceptibility to subsequent influenza disease. Similarly, the cytokines that are induced during in vivo infection, including interferon, could act on cells other than those examined in this manuscript (epithelia and monocytes); such cells could significantly influence resistance to influenza co-infection. Despite these concerns, the manuscript represents a scientifically rigorous and highly novel study that will inform future investigations.

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