SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein.

Autor: Albornoz EA; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, St Lucia, QLD, 4072, Australia., Amarilla AA; School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, 4072, Australia., Modhiran N; School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, 4072, Australia.; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD, 4072, Australia., Parker S; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, St Lucia, QLD, 4072, Australia., Li XX; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, St Lucia, QLD, 4072, Australia., Wijesundara DK; School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, 4072, Australia.; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD, 4072, Australia.; Vaxxas Pty. Ltd., Woolloongabba, QLD, 4102, Australia., Aguado J; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD, 4072, Australia., Zamora AP; School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, 4072, Australia., McMillan CLD; School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, 4072, Australia., Liang B; School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, 4072, Australia., Peng NYG; School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, 4072, Australia., Sng JDJ; School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, 4072, Australia., Saima FT; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, St Lucia, QLD, 4072, Australia., Fung JN; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, St Lucia, QLD, 4072, Australia., Lee JD; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, St Lucia, QLD, 4072, Australia., Paramitha D; School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, 4072, Australia., Parry R; School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, 4072, Australia., Avumegah MS; School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, 4072, Australia.; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD, 4072, Australia., Isaacs A; School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, 4072, Australia., Lo MW; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, St Lucia, QLD, 4072, Australia., Miranda-Chacon Z; Institute of Medicine, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile.; Molecular Medicine Laboratory, Medical School, Universidad de Costa Rica, San Pedro, Costa Rica., Bradshaw D; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, St Lucia, QLD, 4072, Australia., Salinas-Rebolledo C; Institute of Medicine, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile., Rajapakse NW; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, St Lucia, QLD, 4072, Australia., Wolvetang EJ; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD, 4072, Australia., Munro TP; School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, 4072, Australia.; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD, 4072, Australia., Rojas-Fernandez A; Institute of Medicine, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile., Young PR; School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, 4072, Australia.; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD, 4072, Australia.; Australian Infectious Disease Research Centre, Global Virus Network Centre of Excellence Brisbane, Brisbane, QLD, 4072 and 4029, Australia., Stacey KJ; School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, 4072, Australia., Khromykh AA; School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, 4072, Australia.; Australian Infectious Disease Research Centre, Global Virus Network Centre of Excellence Brisbane, Brisbane, QLD, 4072 and 4029, Australia., Chappell KJ; School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, 4072, Australia.; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD, 4072, Australia.; Australian Infectious Disease Research Centre, Global Virus Network Centre of Excellence Brisbane, Brisbane, QLD, 4072 and 4029, Australia., Watterson D; School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, 4072, Australia. d.watterson@uq.edu.au., Woodruff TM; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, St Lucia, QLD, 4072, Australia. t.woodruff@uq.edu.au.; Queensland Brain Institute, University of Queensland, St Lucia, QLD, 4072, Australia. t.woodruff@uq.edu.au.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2023 Jul; Vol. 28 (7), pp. 2878-2893. Date of Electronic Publication: 2022 Nov 01.
DOI: 10.1038/s41380-022-01831-0
Abstrakt: Coronavirus disease-2019 (COVID-19) is primarily a respiratory disease, however, an increasing number of reports indicate that SARS-CoV-2 infection can also cause severe neurological manifestations, including precipitating cases of probable Parkinson's disease. As microglial NLRP3 inflammasome activation is a major driver of neurodegeneration, here we interrogated whether SARS-CoV-2 can promote microglial NLRP3 inflammasome activation. Using SARS-CoV-2 infection of transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) as a COVID-19 pre-clinical model, we established the presence of virus in the brain together with microglial activation and NLRP3 inflammasome upregulation in comparison to uninfected mice. Next, utilising a model of human monocyte-derived microglia, we identified that SARS-CoV-2 isolates can bind and enter human microglia in the absence of viral replication. This interaction of virus and microglia directly induced robust inflammasome activation, even in the absence of another priming signal. Mechanistically, we demonstrated that purified SARS-CoV-2 spike glycoprotein activated the NLRP3 inflammasome in LPS-primed microglia, in a ACE2-dependent manner. Spike protein also could prime the inflammasome in microglia through NF-κB signalling, allowing for activation through either ATP, nigericin or α-synuclein. Notably, SARS-CoV-2 and spike protein-mediated microglial inflammasome activation was significantly enhanced in the presence of α-synuclein fibrils and was entirely ablated by NLRP3-inhibition. Finally, we demonstrate SARS-CoV-2 infected hACE2 mice treated orally post-infection with the NLRP3 inhibitory drug MCC950, have significantly reduced microglial inflammasome activation, and increased survival in comparison with untreated SARS-CoV-2 infected mice. These results support a possible mechanism of microglial innate immune activation by SARS-CoV-2, which could explain the increased vulnerability to developing neurological symptoms akin to Parkinson's disease in COVID-19 infected individuals, and a potential therapeutic avenue for intervention.
(© 2022. The Author(s).)
Databáze: MEDLINE
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