SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike-ACE2 receptor interaction

Albornoz, E. A.; Amarilla, A. A.; Modhiran, N.; Parker, S.; Li, X. X.; Wijesundara, D. K.; Pliego Zamora, A.; McMillan, C. L.; Liang, B.; Peng, N. Y. G.; Sng, J. D. J.; Tuj Saima, F.; Paramitha, D.; Parry, R.; Avumegah, M. S.; Isaacs, A.; Lo, M.; Miranda-Chacon, Z.; Bradshaw, D.; Salinas-Rebolledo, C.; Rajapakse, N. W.; Munro, T.; Rojas-Fernandez, A.; Young, P. R.; Stacey, K. J.; Khromykh, A. A.; Chappell, K. J.; Watterson, D.; Woodruff, T. M.

doi:10.1101/2022.01.11.475947

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bioRxiv · 10.1101/2022.01.11.475947

SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike-ACE2 receptor interaction

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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 Parkinsons 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 utilising a model of human monocyte-derived microglia. We identified that SARS-CoV-2 isolates can bind and enter microglia, triggering inflammasome activation in the absence of viral replication. Mechanistically, microglial NLRP3 could be both primed and activated with SARS-CoV-2 spike glycoprotein in a NF-{kappa}B and ACE2-dependent manner. Notably, virus- and spike protein-mediated inflammasome activation in microglia was significantly enhanced in the presence of -synuclein fibrils, which was entirely ablated by NLRP3-inhibition. These results support a possible mechanism of microglia activation by SARS-CoV-2, which could explain the increased vulnerability to developing neurological symptoms akin to Parkinsons disease in certain COVID-19 infected individuals, and a potential therapeutic avenue for intervention. SIGNIFICANCE STATEMENTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) principally affects the lungs, however there is evidence that the virus can also reach the brain and lead to chronic neurological symptoms. In this study, we examined the interaction SARS-CoV-2 with brain immune cells, by using an ex-vivo model of human monocyte-derived microglia. We identified robust activation of the innate immune sensor complex, NLRP3 inflammasome, in cells exposed to SARS-CoV-2. This was dependent on spike protein-ACE2 receptor interaction and was potentiated in the presence of -synuclein. We therefore identify a possible mechanism for SARS-CoV-2 and increased vulnerability to developing neurological dysfunction. These findings support a potential therapeutic avenue for treatment of SARS-CoV-2 driven neurological manifestations, through use of NLRP3 inflammasome or ACE2 inhibitors.

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Albornoz, E. A., Amarilla, A. A., Modhiran, N., Parker, S., Li, X. X., Wijesundara, D. K., Pliego Zamora, A., McMillan, C. L., Liang, B., Peng, N. Y. G., Sng, J. D. J., Tuj Saima, F., Paramitha, D., Parry, R., Avumegah, M. S., Isaacs, A., Lo, M., Miranda-Chacon, Z., Bradshaw, D., Salinas-Rebolledo, C., Rajapakse, N. W., Munro, T., Rojas-Fernandez, A., Young, P. R., Stacey, K. J., Khromykh, A. A., Chappell, K. J., Watterson, D., Woodruff, T. M.. 2022-01-12. SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike-ACE2 receptor interaction. https://doi.org/10.1101/2022.01.11.475947

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