Murine norovirus infection of macrophages induces intrinsic apoptosis as the major form of programmed cell death

Joshua M Deerain; Turgut E Aktepe; Alice M Trenerry; Gregor Ebert; Jennifer L Hyde; Katelyn Charry; Laura Edgington-Mitchell; Banyan Xu; Rebecca L Ambrose; Soroush T Sarvestani; Kate E Lawlor; Jaclyn S Pearson; Peter A White; Jason M Mackenzie

doi:10.1016/j.virol.2023.109921

Murine norovirus infection of macrophages induces intrinsic apoptosis as the major form of programmed cell death

Virology. 2024 Jan:589:109921. doi: 10.1016/j.virol.2023.109921. Epub 2023 Oct 31.

Affiliations

¹ Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, VIC, 3000, Australia.
² The Walter and Elisa Hall Institute, Melbourne, VIC, 3052, Australia; Department of Medical Biology, University of Melbourne, VIC, 3050, Australia.
³ Department of Microbiology, School of Medicine, University of Washington, Seattle, USA.
⁴ Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC, 3010, Australia.
⁵ Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, 3168, Australia.
⁶ The Walter and Elisa Hall Institute, Melbourne, VIC, 3052, Australia; Department of Medical Biology, University of Melbourne, VIC, 3050, Australia; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, 3168, Australia; Department of Molecular and Translational Science, Monash University, Melbourne, VIC, 3168, Australia.
⁷ Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, 3168, Australia; Department of Molecular and Translational Science, Monash University, Melbourne, VIC, 3168, Australia; Department of Microbiology, Monash University, Melbourne, VIC, 3168, Australia.
⁸ School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
⁹ Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, VIC, 3000, Australia. Electronic address: jason.mackenzie@unimelb.edu.au.

PMID: 37939648
DOI: 10.1016/j.virol.2023.109921

Abstract

Human norovirus is the leading cause of acute gastroenteritis worldwide, however despite the significance of this pathogen, we have a limited understanding of how noroviruses cause disease, and modulate the innate immune response. Programmed cell death (PCD) is an important part of the innate response to invading pathogens, but little is known about how specific PCD pathways contribute to norovirus replication. Here, we reveal that murine norovirus (MNV) virus-induced PCD in macrophages correlates with the release of infectious virus. We subsequently show, genetically and chemically, that MNV-induced cell death and viral replication occurs independent of the activity of inflammatory mediators. Further analysis revealed that MNV infection promotes the cleavage of apoptotic caspase-3 and PARP. Correspondingly, pan-caspase inhibition, or BAX and BAK deficiency, perturbed viral replication rates and delayed virus release and cell death. These results provide new insights into how MNV harnesses cell death to increase viral burden.

Keywords: Apoptosis; Macrophage; Murine norovirus; Norovirus; Programmed cell death.

MeSH terms

Animals
Apoptosis
Caliciviridae Infections*
Humans
Immunity, Innate
Macrophages
Mice
Norovirus* / physiology
Virus Replication