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Review 2: "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 2: "Omicron-induced interferon signalling prevents influenza A virus infection"
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key-enterThis Pub is a Review of
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:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review:

In the preprint titled “Omicron-induced interferon signalling prevents influenza A virus infection”, the authors investigated the differential immune responses elicited by the SARS-CoV-2 Delta and Omicron variants in human bronchial epithelial cells. Consistent with previous reports, the authors showed that the Omicron variant replicated faster in the upper airway compared to the Delta variant. Similar studies have also investigated the sensitivity of the Omicron variant to type I Interferon expression (IFN-I) and showed that the Omicron variant is more resistant to IFN-I treatment compared to the previous variants. This is in line with the authors’ findings where the Omicron variant induces IFN-I expression in infected HBE cells without significant compromise in virus replication. The evidence presented by the authors robustly indicates that the Omicron variant induced IFN-I expression after infection of HBE cells which is distinct from the Delta variant. One curious observation is that the Omicron and Delta variant induce comparable levels of expression of proteins involved in IFN signaling except for ISG15 at the peak of viral RNA levels. This would suggest that ISG15 may play a role in the variant-specific role in inducing IFN-I expression which merits further investigation.

The authors nicely showed that IAV infection is blocked by prior Omicron but not Delta infection. The effects of IAV blockade by prior Omicron infection are mediated by IFN-I signaling. The authors provided very robust evidence to point out the distinct IFN-I expression pattern in Omicron- and Delta-infected cells, which explains the subsequent blockade of IAV infection. Also, the authors’ finding is consistent with other recently published reports showing that the Omicron variant has evolved to suppress IFN-I expression. However, it is difficult to discern the actual role of prior Omicron infection in protecting subsequent IAV infection as there is little to no clinical evidence supporting the hypothesis. Other factors such as public health measures to quench the spread of Omicron could possibly explain the decline of influenza-like illness during the Omicron wave. Despite the robust evidence presented by the authors in HBE cultures, further analysis is required to show the casual relationship to support the role of prior Omicron infection in protecting against subsequent IAV infection, as the authors suggested. It would also be important to investigate if this is an IAV-specific phenotype or if it is applicable to all pathogens sensitive to IFN-I-mediated protection.

It is unclear how many donors were involved in this study for generating HBE cells. From my understating, the HBE cells used in this manuscript were derived from a single donor. It may be important to include additional donors to show that this is not a donor-specific phenotype. Also, the authors only measured viral RNA levels as a surrogate for infectious virus titers. It would be important to measure actual infectious virus titers as viral RNA does not reflect actual infectious viruses. Overall, the manuscript is logical and supports the authors’ hypothesis that prior Omicron infection but not Delta infection protected cells from subsequent IAV infection, however, the role of Omicron-induced IFN in protecting against IAV infection in the real world requires further experimental evidence.

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