RIG-I-induced innate antiviral immunity protects mice from lethal SARS-CoV-2 infection

Samira Marx; Beate M Kümmerer; Christian Grützner; Hiroki Kato; Martin Schlee; Marcel Renn; Eva Bartok; Gunther Hartmann

doi:10.1016/j.omtn.2022.02.008

RIG-I-induced innate antiviral immunity protects mice from lethal SARS-CoV-2 infection

Mol Ther Nucleic Acids. 2022 Mar 8:27:1225-1234. doi: 10.1016/j.omtn.2022.02.008. Epub 2022 Feb 13.

Authors

Samira Marx¹, Beate M Kümmerer^{2

3}, Christian Grützner¹, Hiroki Kato⁴, Martin Schlee¹, Marcel Renn^{1

5}, Eva Bartok^{1

6}, Gunther Hartmann^{1

3}

Affiliations

¹ Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, 53127 Bonn, Germany.
² Institute of Virology, University Hospital Bonn, 53127 Bonn, Germany.
³ German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, 53127 Bonn, Germany.
⁴ Institute of Cardiovascular Immunology, University Hospital Bonn, 53127 Bonn, Germany.
⁵ Mildred Scheel School of Oncology, University Hospital Bonn, 53127 Bonn, Germany.
⁶ Unit of Experimental Immunology, Department of Biomedical Sciences, Institute of Tropical Medicine, 2000 Antwerp, Belgium.

Abstract

The SARS-CoV-2 pandemic has underscored the need for rapidly usable prophylactic and antiviral treatments against emerging viruses. The targeted stimulation of antiviral innate immune receptors can trigger a broad antiviral response that also acts against new, unknown viruses. Here, we used the K18-hACE2 mouse model of COVID-19 to examine whether activation of the antiviral RNA receptor RIG-I protects mice from lethal SARS-CoV-2 infection and reduces disease severity. We found that prophylactic, systemic treatment of mice with the specific RIG-I ligand 3pRNA, but not type I interferon, 1-7 days before viral challenge, improved survival of mice by up to 50%. Survival was also improved with therapeutic 3pRNA treatment starting 1 day after viral challenge. This improved outcome was associated with lower viral load in oropharyngeal swabs and in the lungs and brains of 3pRNA-treated mice. Moreover, 3pRNA-treated mice exhibited reduced lung inflammation and developed a SARS-CoV-2-specific neutralizing antibody response. These results demonstrate that systemic RIG-I activation by therapeutic RNA oligonucleotide agonists is a promising strategy to convey effective, short-term antiviral protection against SARS-CoV-2 infection, and it has great potential as a broad-spectrum approach to constrain the spread of newly emerging viruses until virus-specific therapies and vaccines become available.

Keywords: COVID-19; K18-hACE2 mouse model; MT: Oligonucleotides: Therapies and Applications; RIG-I; SARS-CoV-2; antiviral immunity; coronavirus; emerging viruses; innate immunity; nucleic acid immunity; pandemic; type I IFN.