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SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein
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 activ...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10615762/ https://www.ncbi.nlm.nih.gov/pubmed/36316366 http://dx.doi.org/10.1038/s41380-022-01831-0 |
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author | Albornoz, Eduardo A. Amarilla, Alberto A. Modhiran, Naphak Parker, Sandra Li, Xaria X. Wijesundara, Danushka K. Aguado, Julio Zamora, Adriana Pliego McMillan, Christopher L. D. Liang, Benjamin Peng, Nias Y. G. Sng, Julian D. J. Saima, Fatema Tuj Fung, Jenny N. Lee, John D. Paramitha, Devina Parry, Rhys Avumegah, Michael S. Isaacs, Ariel Lo, Martin W. Miranda-Chacon, Zaray Bradshaw, Daniella Salinas-Rebolledo, Constanza Rajapakse, Niwanthi W. Wolvetang, Ernst J. Munro, Trent P. Rojas-Fernandez, Alejandro Young, Paul R. Stacey, Katryn J. Khromykh, Alexander A. Chappell, Keith J. Watterson, Daniel Woodruff, Trent M. |
author_facet | Albornoz, Eduardo A. Amarilla, Alberto A. Modhiran, Naphak Parker, Sandra Li, Xaria X. Wijesundara, Danushka K. Aguado, Julio Zamora, Adriana Pliego McMillan, Christopher L. D. Liang, Benjamin Peng, Nias Y. G. Sng, Julian D. J. Saima, Fatema Tuj Fung, Jenny N. Lee, John D. Paramitha, Devina Parry, Rhys Avumegah, Michael S. Isaacs, Ariel Lo, Martin W. Miranda-Chacon, Zaray Bradshaw, Daniella Salinas-Rebolledo, Constanza Rajapakse, Niwanthi W. Wolvetang, Ernst J. Munro, Trent P. Rojas-Fernandez, Alejandro Young, Paul R. Stacey, Katryn J. Khromykh, Alexander A. Chappell, Keith J. Watterson, Daniel Woodruff, Trent M. |
author_sort | Albornoz, Eduardo A. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10615762 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-106157622023-11-01 SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein Albornoz, Eduardo A. Amarilla, Alberto A. Modhiran, Naphak Parker, Sandra Li, Xaria X. Wijesundara, Danushka K. Aguado, Julio Zamora, Adriana Pliego McMillan, Christopher L. D. Liang, Benjamin Peng, Nias Y. G. Sng, Julian D. J. Saima, Fatema Tuj Fung, Jenny N. Lee, John D. Paramitha, Devina Parry, Rhys Avumegah, Michael S. Isaacs, Ariel Lo, Martin W. Miranda-Chacon, Zaray Bradshaw, Daniella Salinas-Rebolledo, Constanza Rajapakse, Niwanthi W. Wolvetang, Ernst J. Munro, Trent P. Rojas-Fernandez, Alejandro Young, Paul R. Stacey, Katryn J. Khromykh, Alexander A. Chappell, Keith J. Watterson, Daniel Woodruff, Trent M. Mol Psychiatry Immediate Communication 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. Nature Publishing Group UK 2022-11-01 2023 /pmc/articles/PMC10615762/ /pubmed/36316366 http://dx.doi.org/10.1038/s41380-022-01831-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Immediate Communication Albornoz, Eduardo A. Amarilla, Alberto A. Modhiran, Naphak Parker, Sandra Li, Xaria X. Wijesundara, Danushka K. Aguado, Julio Zamora, Adriana Pliego McMillan, Christopher L. D. Liang, Benjamin Peng, Nias Y. G. Sng, Julian D. J. Saima, Fatema Tuj Fung, Jenny N. Lee, John D. Paramitha, Devina Parry, Rhys Avumegah, Michael S. Isaacs, Ariel Lo, Martin W. Miranda-Chacon, Zaray Bradshaw, Daniella Salinas-Rebolledo, Constanza Rajapakse, Niwanthi W. Wolvetang, Ernst J. Munro, Trent P. Rojas-Fernandez, Alejandro Young, Paul R. Stacey, Katryn J. Khromykh, Alexander A. Chappell, Keith J. Watterson, Daniel Woodruff, Trent M. SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein |
title | SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein |
title_full | SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein |
title_fullStr | SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein |
title_full_unstemmed | SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein |
title_short | SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein |
title_sort | sars-cov-2 drives nlrp3 inflammasome activation in human microglia through spike protein |
topic | Immediate Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10615762/ https://www.ncbi.nlm.nih.gov/pubmed/36316366 http://dx.doi.org/10.1038/s41380-022-01831-0 |
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