Small molecules inhibit SARS-COV-2 induced aberrant inflammation and viral replication in mice by targeting S100A8/A9-TLR4 axis

Guo, Q.; Zhao, Y.; Li, J.; Liu, J.; Qin, C.; Wang, X.; You, F.; Guo, X.; Zhang, Z.; Cao, L.; Luo, Y.; Wei, X.; Chen, L.; Bao, L.; Deng, W.; Zhu, H.; Gao, R.

doi:10.1101/2020.09.09.288704

bioRxiv · 10.1101/2020.09.09.288704

Small molecules inhibit SARS-COV-2 induced aberrant inflammation and viral replication in mice by targeting S100A8/A9-TLR4 axis

Guo, Q.·Zhao, Y.·Li, J.·Liu, J.·Qin, C.·Wang, X.·You, F.·Guo, X.·Zhang, Z.·Cao, L.·Luo, Y.·Wei, X.·Chen, L.·Bao, L.·Deng, W.·Zhu, H.·Gao, R.

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Abstract

The SARS-CoV-2 pandemic poses an unprecedented public health crisis. Accumulating evidences suggest that SARS-CoV-2 infection causes dysregulation of immune system. However, the unique signature of early immune responses remains elusive. We characterized the transcriptome of rhesus macaques and mice infected with SARS-CoV-2. Alarmin S100A8 was robustly induced by SARS-CoV-2 in animal models as well as in COVID-19 patients. Paquinimod, a specific inhibitor of S100A8/A9, could reduce inflammatory response and rescue the pneumonia with substantial reduction of viral titers in SASR-CoV-2 infected animals. Remarkably, Paquinimod treatment resulted in 100% survival of mice in a lethal model of mouse coronavirus (MHV) infection. A novel group of neutrophils that contributed to the uncontrolled inflammation and onset of COVID-19 were dramatically induced by coronavirus infections. Paquinimod treatment could reduce these neutrophils and regain antiviral responses, unveiling key roles of S100A8/A9 and noncanonical neutrophils in the pathogenesis of COVID-19, highlighting new opportunities for therapeutic intervention.

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Guo, Q., Zhao, Y., Li, J., Liu, J., Qin, C., Wang, X., You, F., Guo, X., Zhang, Z., Cao, L., Luo, Y., Wei, X., Chen, L., Bao, L., Deng, W., Zhu, H., Gao, R.. 2020-09-09. Small molecules inhibit SARS-COV-2 induced aberrant inflammation and viral replication in mice by targeting S100A8/A9-TLR4 axis. https://doi.org/10.1101/2020.09.09.288704

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