Journal article
Necroptosis does not drive disease pathogenesis in a mouse infective model of SARS-CoV-2 in vivo
SM Bader, JP Cooney, R Bhandari, L Mackiewicz, M Dayton, D Sheerin, SR Georgy, JM Murphy, KC Davidson, CC Allison, M Pellegrini, M Doerflinger
Cell Death and Disease | SPRINGERNATURE | Published : 2024
Open access
Abstract
Necroptosis, a type of lytic cell death executed by the pseudokinase Mixed Lineage Kinase Domain-Like (MLKL) has been implicated in the detrimental inflammation caused by SARS-CoV-2 infection. We minimally and extensively passaged a single clinical SARSCoV-2 isolate to create models of mild and severe disease in mice allowing us to dissect the role of necroptosis in SARS-CoV-2 disease pathogenesis. We infected wild-type and MLKL-deficient mice and found no significant differences in viral loads or lung pathology. In our model of severe COVID-19, MLKL-deficiency did not alter the host response, ameliorate weight loss, diminish systemic pro-inflammatory cytokines levels, or prevent lethality i..
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Awarded by Doherty Institute
Funding Acknowledgements
This work was supported by National Health and Medical Research Council Australia (NHMRC) Investigator grant GNT1175011 to M.Pellegrini, GNT1172929 to JMM, and the Victorian State Government Operational Infrastructure Support and the Independent Research Institutes Infrastructure Support Scheme of the Australian Government National Health and Medical Research Council (GNT9000719). We thank Esther Bandala Sanchez for expert advice with ELISA experiments and Andre Samson for providing antibodies for western blot. We further thank Genentech for providing the p-mRIPK3 antibody used for western blots. Dan Fayle, Lauren Wilkins and Thomas Kapitelli for excellent animal husbandry support. We would also like to thank the Walter and Eliza Hall histology and imaging departments for their services. The authors acknowledge the contribution and assistance of Melbourne Health through its Victorian Infectious Diseases Reference Laboratory at the Doherty Institute, in providing our laboratory with isolated SARS-CoV-2 material.