Expression of a Functional Mx1 Protein Is Essential for the Ability of RIG-I Agonist Prophylaxis to Provide Potent and Long-Lasting Protection in a Mouse Model of Influenza A Virus Infection

Lara S U Schwab; Fernando Villalón-Letelier; Melkamu B Tessema; Sarah L Londrigan; Andrew G Brooks; Aeron Hurt; Christoph Coch; Thomas Zillinger; Gunther Hartmann; Patrick C Reading

doi:10.3390/v14071547

Expression of a Functional Mx1 Protein Is Essential for the Ability of RIG-I Agonist Prophylaxis to Provide Potent and Long-Lasting Protection in a Mouse Model of Influenza A Virus Infection

Viruses. 2022 Jul 15;14(7):1547. doi: 10.3390/v14071547.

Authors

Affiliations

¹ Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne, VIC 3000, Australia.
² Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, 53127 Bonn, Germany.
³ WHO Collaborating Centre for Reference and Research on Influenza, Victorian Infectious Diseases Reference Laboratory at the Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne, VIC 3000, Australia.

Abstract

RIG-I is an innate sensor of RNA virus infection and its activation induces interferon-stimulated genes (ISGs). In vitro studies using human cells have demonstrated the ability of synthetic RIG-I agonists (3pRNA) to inhibit IAV replication. However, in mouse models of IAV the effectiveness of 3pRNA reported to date differs markedly between studies. Myxoma resistance (Mx)1 is an ISG protein which mediates potent anti-IAV activity, however most inbred mouse strains do not express a functional Mx1. Herein, we utilised C57BL/6 mice that do (B6.A2G-Mx1) and do not (B6-WT) express functional Mx1 to assess the ability of prophylactic 3pRNA treatment to induce ISGs and to protect against subsequent IAV infection. In vitro, 3pRNA treatment of primary lung cells from B6-WT and B6.A2G-Mx1 mice resulted in ISG induction however inhibition of IAV infection was more potent in cells from B6.A2G-Mx1 mice. In vivo, a single intravenous injection of 3pRNA resulted in ISG induction in lungs of both B6-WT and B6.A2G-Mx1 mice, however potent and long-lasting protection against subsequent IAV challenge was only observed in B6.A2G-Mx1 mice. Thus, despite broad ISG induction, expression of a functional Mx1 is critical for potent and long-lasting RIG-I agonist-mediated protection in the mouse model of IAV infection.

Keywords: Mx; RIG-I; influenza; innate immunity; mouse model.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antiviral Agents
DEAD Box Protein 58*
Influenza A virus
Interferons
Mice
Mice, Inbred C57BL
Mice, Inbred Strains
Myxovirus Resistance Proteins* / genetics
Orthomyxoviridae Infections*
Proteins

Substances

Antiviral Agents
Mx1 protein, mouse
Myxovirus Resistance Proteins
Proteins
Interferons
Ddx58 protein, mouse
DEAD Box Protein 58

Grants and funding

This research was funded by the National Health and Medical Research Council (NHMRC) of Australia (Project Grant APP1143154) to P.C.R. and S.L.L. The Melbourne WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health. Additionally, this work was supported by the German Center for Infectious Diseases (DZIF) TTU 07.834_00 to G.H, and by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Project ID 369799452—TRR237 to G.H. and T.Z., and under Germany’s Excellence Strategy–EXC2151–390873048, of which G.H. is a member.