Induction of alarmin S100A8/A9 mediates activation of aberrant neutrophils in the pathogenesis of COVID-19

Guo, Qirui; Zhao, Yingchi; Li, Junhong; Liu, Jiangning; Yang, Xiuhong; Guo, Xuefei; Kuang, Ming; Xia, Huawei; Zhang, Zeming; Cao, Lili; Luo, Yujie; Bao, Linlin; Wang, Xiao; Wei, Xuemei; Deng, Wei; Wang, Nan; Chen, Luoying; Chen, Jingxuan; Zhu, Hua; Gao, Ran; Qin, Chuan; Wang, Xiangxi; You, Fuping

The SARS-CoV-2 pandemic poses an unprecedented public health crisis. Evidence suggests that SARS-CoV-2 infection causes dysregulation of the 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 in SARS-CoV-2 infected animal models as well as in COVID-19 patients. Paquinimod, a specific inhibitor of S100A8/A9, could rescue the pneumonia with substantial reduction of viral loads in SARS-CoV-2 infected mice. Remarkably, Paquinimod treatment resulted in almost 100% survival in a lethal model of mouse coronavirus infection using the mouse hepatitis virus (MHV). A group of neutrophils that contributes to the uncontrolled pathological damage and onset of COVID-19 were dramatically induced by coronavirus infection. Paquinimod treatment could reduce these neutrophils and regain antiviral responses, unveiling key roles of S100A8/A9 and aberrant neutrophils in the pathogenesis of COVID-19, highlighting new opportunities for therapeutic intervention.