iScience
Volume 26, Issue 1, 20 January 2023, 105742
Journal home page for iScience

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

https://doi.org/10.1016/j.isci.2022.105742Get rights and content
Under a Creative Commons license
open access

Highlights

  • SARS-CoV-2 overproduces small viral RNAs encoding exact 5′ end genome in human cells

  • The 5′ end small viral RNAs are RIG-I stimulatory and act as IFN/cytokine agonists

  • The 5′ end svRNA accumulates in cells in vitro and ex vivo at late infection stages

  • svRNA accumulation in cells may confer delayed IFN response as in severe COVID-19

Summary

Patients with severe COVID-19 exhibit a cytokine storm characterized by greatly elevated levels of cytokines. Despite this, the interferon (IFN) response is delayed, contributing to disease progression. Here, we report that SARS-CoV-2 excessively generates small viral RNAs (svRNAs) encoding exact 5′ ends of positive-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 5′ end svRNAs are RIG-I agonists and induce the IFN-β response in the later stages of infection. The first 60-nt ends bearing duplex structures and 5′-triphosphates are responsible for immune-stimulation. We propose that RIG-I activation by accumulated SARS-CoV-2 5′ 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.

Subject areas

immunology and virology

Data and code availability

Data reported in the study are available from the lead contact upon request. This paper doses not report original code. Any additional information required to reanalyse the data reported in this paper is available from the lead contact upon request.

Cited by (0)

6

These authors contributed equally

7

Lead contact