Cytomegalovirus-induced peroxynitrite promotes virus entry and contributes to pathogenesis in a murine model of infection

Amratia, Pragati S., Kerr-Jones, Lauren E., Chapman, Lucy, Marsden, Morgan, Clement, Mathew ORCID: https://orcid.org/0000-0002-9280-5281, Stanton, Richard J. ORCID: https://orcid.org/0000-0002-6799-1182 and Humphreys, Ian R. ORCID: https://orcid.org/0000-0002-9512-5337 2024. Cytomegalovirus-induced peroxynitrite promotes virus entry and contributes to pathogenesis in a murine model of infection. mBio 15 (8) , e03152-23. 10.1128/mbio.03152-23

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Abstract

There are no licensed vaccines for human cytomegalovirus (HCMV), and current antiviral drugs that target viral proteins are toxic and prone to resistance. Targeting host pathways essential for virus replication provides an alternate strategy that may reduce opportunities for drug resistance to occur. Oxidative stress is triggered by numerous viruses including HCMV. Peroxynitrite is a reactive nitrogen species that is formed during oxidative stress. Herein, we identified that HCMV rapidly induces the generation of intracellular peroxynitrite upon infection in a manner partially dependent upon xanthine oxidase generation. Peroxynitrite promoted HCMV infection in both cell-free and cell-associated infection systems in multiple cell types. Inhibiting peroxynitrite within the first 24 hours of infection prevented HCMV replication and peroxynitrite promoted cell entry and pp65 translocation into the host cell nuclei. Furthermore, using the murine cytomegalovirus model, we demonstrated that antagonizing peroxynitrite significantly reduces cytomegalovirus replication and pathogenesis in vivo. Overall, our study highlights a proviral role for peroxynitrite in CMV infection and implies that RNS and/or the mechanisms that induce their production could be targeted as a novel strategy to inhibit HCMV infection.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Publisher:	American Society for Microbiology
ISSN:	2161-2129
Funders:	Wellcome Trust, MRC
Date of First Compliant Deposit:	3 July 2024
Date of Acceptance:	4 June 2024
Last Modified:	05 Nov 2024 11:15
URI:	https://orca.cardiff.ac.uk/id/eprint/169697

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