A stem-loop RNA RIG-I agonist protects against acute and chronic SARS-CoV-2 infection in mice
Open Access
- 10 November 2021
- journal article
- research article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 219 (1)
- https://doi.org/10.1084/jem.20211818
Abstract
As SARS-CoV-2 continues to cause morbidity and mortality around the world, there is an urgent need for the development of effective medical countermeasures. Here, we assessed the antiviral capacity of a minimal RIG-I agonist, stem-loop RNA 14 (SLR14), in viral control, disease prevention, post-infection therapy, and cross-variant protection in mouse models of SARS-CoV-2 infection. A single dose of SLR14 prevented viral infection in the lower respiratory tract and development of severe disease in a type I interferon (IFN-I)–dependent manner. SLR14 demonstrated remarkable prophylactic protective capacity against lethal SARS-CoV-2 infection and retained considerable efficacy as a therapeutic agent. In immunodeficient mice carrying chronic SARS-CoV-2 infection, SLR14 elicited near-sterilizing innate immunity in the absence of the adaptive immune system. In the context of infection with variants of concern (VOCs), SLR14 conferred broad protection against emerging VOCs. These findings demonstrate the therapeutic potential of SLR14 as a host-directed, broad-spectrum antiviral for early post-exposure treatment and treatment of chronically infected immunosuppressed patients.Keywords
Funding Information
- Women’s Health Research at Yale Pilot Project Program
- Mathers Family Foundation
- Ludwig Family Foundation
- National Institute of Allergy and Infectious Diseases (1R01AI157488-01, 5R01AI127429-04)
- Burroughs Wellcome Fund
- Emergent Ventures
- National Institute of Allergy and Infectious Diseases (T32AI007019)
- National Institute of Allergy and Infectious Diseases (2T32AI007517-16, K08AI163493)
- Pew Charitable Trusts
- Netherlands Organization for Scientific Research (019.181EN.004)
- National Institute of Allergy and Infectious Diseases (K08AI128043)
- Howard Hughes Medical Institute
This publication has 69 references indexed in Scilit:
- Design of amidobenzimidazole STING receptor agonists with systemic activityNature, 2018
- A minimal RNA ligand for potent RIG-I activation in living miceScience Advances, 2018
- Control of adaptive immunity by the innate immune systemNature Immunology, 2015
- Nucleic acid-induced antiviral immunity in invertebrates: An evolutionary perspectiveDevelopmental & Comparative Immunology, 2015
- Interferon-Stimulated Genes: A Complex Web of Host DefensesAnnual Review of Immunology, 2014
- Systems Analysis of a RIG-I Agonist Inducing Broad Spectrum Inhibition of Virus InfectivityPLoS Pathogens, 2013
- Anti-interferon-α neutralizing antibody is associated with nonresponse to pegylated interferon-α plus ribavirin in chronic hepatitis CJournal of Viral Hepatitis, 2012
- Structural Insights into RNA Recognition by RIG-ICell, 2011
- Lethal Infection of K18- hACE2 Mice Infected with Severe Acute Respiratory Syndrome CoronavirusJournal of Virology, 2007
- Neutralising antibodies to interferon beta during the treatment of multiple sclerosisJournal of Neurology, Neurosurgery & Psychiatry, 2002