4.7 Article

Stimulation of interferon-b responses by aberrant SARS-CoV-2 small viral RNAs acting as retinoic acid-inducible gene-I agonists

Journal

ISCIENCE
Volume 26, Issue 1, Pages -

Publisher

CELL PRESS
DOI: 10.1016/j.isci.2022.105742

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Patients with severe COVID-19 exhibit elevated levels of cytokines and delayed interferon response. The study finds that SARS-CoV-2 generates excessive small viral RNAs encoding the 50 ends of positive-sense genes, which can stimulate the immune response. It suggests that RIG-I activation by accumulated SARS-CoV-2 50 end svRNAs may contribute to over-exuberant IFN production and the weaker immune response in less pathogenic coronaviruses may be due to lower svRNA production during replication.
Patients with severe COVID-19 exhibit a cytokine storm characterized by greatly elevated levels of cytokines. Despite this, the interferon (IFN) response is de-layed, contributing to disease progression. Here, we report that SARS-CoV-2 excessively generates small viral RNAs (svRNAs) encoding exact 50 ends of posi-tive-sense genes in human cells in vitro and ex vivo, whereas endemic human coronaviruses (OC43 and 229E) produce significantly fewer similar svRNAs. SARS-CoV-2 50 end svRNAs are RIG-I agonists and induce the IFN-b response in the later stages of infection. The first 60-nt ends bearing duplex structures and 50-triphosphates are responsible for immune-stimulation. We propose that RIG-I activation by accumulated SARS-CoV-2 50 end svRNAs may contribute to later drive over-exuberant IFN production. Additionally, the differences in the amounts of svRNAs produced and the corresponding IFN response among CoV strains suggest that lower svRNA production during replication may correlate with the weaker immune response seen in less pathogenic CoVs.

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