SARM1 depletion slows axon degeneration in a CNS model of neurotropic viral infection

Crawford, C. L. et al. (2022) SARM1 depletion slows axon degeneration in a CNS model of neurotropic viral infection. Frontiers in Molecular Neuroscience, 15, 860410. (doi: 10.3389/fnmol.2022.860410) (PMID:35493328) (PMCID:PMC9043327)

Abstract

Zika virus (ZIKV) is a neurotropic flavivirus recently linked to congenital ZIKV syndrome in children and encephalitis and Guillain-Barré syndrome in adults. Neurotropic viruses often use axons to traffic to neuronal or glial cell somas where they either remain latent or replicate and proceed to infect new cells. Consequently, it has been suggested that axon degeneration could represent an evolutionarily conserved mechanism to limit viral spread. Whilst it is not known if ZIKV transits in axons, we previously reported that ZIKV infection of glial cells in a murine spinal cord-derived cell culture model of the CNS is associated with a profound loss of neuronal cell processes. This, despite that postmitotic neurons are relatively refractory to infection and death. Here, we tested the hypothesis that ZIKV-associated degeneration of neuronal processes is dependent on activation of Sterile alpha and armadillo motif-containing protein 1 (SARM1), an NADase that acts as a central executioner in a conserved axon degeneration pathway. To test this, we infected wild type and Sarm1 homozygous or heterozygous null cell cultures with ZIKV and examined NAD+ levels as well as the survival of neurons and their processes. Unexpectedly, ZIKV infection led to a rapid SARM1-independent reduction in NAD+. Nonetheless, the subsequent profound loss of neuronal cell processes was SARM1-dependent and was preceded by early changes in the appearance of β-tubulin III staining. Together, these data identify a role for SARM1 in the pathogenesis of ZIKV infection, which may reflect SARM1's conserved prodegenerative function, independent of its NADase activity.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Komarek, Miss Lina and Montague, Dr Paul and Crawford, Colin and Willison, Professor Hugh and Barnett, Professor Susan and Linington, Professor Christopher and Schultz, Dr Verena and Edgar, Professor Julia and Donald, Dr Claire and Kohl, Professor Alain
• Authors: Crawford, C. L., Antoniou, C., Komarek, L., Schultz, V., Donald, C. L., Montague, P., Barnett, S. C., Linington, C., Willison, H. J., Kohl, A., Coleman, M. P., and Edgar, J. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research; College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• Journal Name: Frontiers in Molecular Neuroscience
• Publisher: Frontiers Media
• ISSN: 1662-5099
• ISSN (Online): 1662-5099
• Copyright Holders: Copyright © 2022 Crawford, Antoniou, Komarek, Schultz, Donald, Montague, Barnett, Linington, Willison, Kohl, Coleman and Edgar
• First Published: First published in Frontiers in Molecular Neuroscience 15: 860410
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
173101		ZikaPLAN	Hugh Willison	European Commission (EC)	Willison, Professor Hugh	III - Immunology
172630007		Arthropod-borne infections and emerging virus infections in high risk areas (Programme 4)	Alain Kohl	Medical Research Council (MRC)	MC_UU_12014/8	III - Centre for Virus Research
172580		The emergence of Zika virus in Brazil: investigating prevalence and host responses to design preventive strategies	Alain Kohl	Medical Research Council (MRC)	MR/N017552/1	III-MRC-GU Centre for Virus Research