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


ABSTRACT: 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.

SUBMITTER: Albornoz EA 

PROVIDER: S-EPMC10615762 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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

Albornoz Eduardo A EA   Amarilla Alberto A AA   Modhiran Naphak N   Parker Sandra S   Li Xaria X XX   Wijesundara Danushka K DK   Aguado Julio J   Zamora Adriana Pliego AP   McMillan Christopher L D CLD   Liang Benjamin B   Peng Nias Y G NYG   Sng Julian D J JDJ   Saima Fatema Tuj FT   Fung Jenny N JN   Lee John D JD   Paramitha Devina D   Parry Rhys R   Avumegah Michael S MS   Isaacs Ariel A   Lo Martin W MW   Miranda-Chacon Zaray Z   Bradshaw Daniella D   Salinas-Rebolledo Constanza C   Rajapakse Niwanthi W NW   Wolvetang Ernst J EJ   Munro Trent P TP   Rojas-Fernandez Alejandro A   Young Paul R PR   Stacey Katryn J KJ   Khromykh Alexander A AA   Chappell Keith J KJ   Watterson Daniel D   Woodruff Trent M TM  

Molecular psychiatry 20221101 7


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 hum  ...[more]

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