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Mapping the interferon response

Cell (2021)

Severe COVID-19 is characterized by the overproduction of inflammatory mediators and cytokines such as interleukin-1 (IL-1), IL-6 and granulocyte–macrophage colony-stimulating factor (GM-CSF); however, the part played by interferons (IFNs) — the signature antiviral cytokines — is complex. In Cell, Zanoni and colleagues investigate the expression of IFNs along the upper and lower respiratory tract (URT and LRT, respectively) to understand their effect on COVID-19 severity. Within the URT of patients under 70, most, but not all, IFNs correlate with viral load; however, viral load in the UTR per se does not correlate with the severity of the disease. By contrast, patients older than 70 show a general dysregulation of IFN production in which even low viral burdens can associate with very high IFN expression. High expression of IFN-III (IFNλ), and to a lesser degree IFN-I (IFNβ), in the URT compared with the LRT associates with a milder disease course. IFNλ1 in particular seems to be beneficial, and efficiently triggers the induction of antiviral genes by human bronchial epithelial cells. Furthermore, high relative expression of IFNs in the LRT associates with the activation of cell death pathways. The URT and LRT also differ in their source of IFN production. In the URT, epithelium is the primary producer of IFNs and this occurs directly in response to SARS-CoV-2 infection. By contrast, in the LRT, hematopoietic cells such as conventional dendritic cells are the main source of IFNs and do so in response to SARS-CoV-2-infected epithelium. This study therefore suggests that a robust and prompt IFN-III response in the URT can reduce CoV-2 infection before it reaches the lungs, where IFNs instead exert an immunopathological role.

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Correspondence to Zoltan Fehervari.

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Fehervari, Z. Mapping the interferon response. Nat Immunol 22, 1198 (2021).

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