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

• Published in: Cell host & microbe Vol. 29; no. 2; pp. 222 - 235.e4
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.02.2021; The Authors. Published by Elsevier Inc
• Subjects: aberrant neutrophils; Alarmins - pharmacology; Animals; Antiviral Agents - pharmacology; COVID-19 - metabolism; COVID-19 - virology; COVID-19 Drug Treatment; Disease Models, Animal; Female; Humans; Macaca mulatta; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils - drug effects; Neutrophils - metabolism; Paquinimod; S100A8/A9; SARS-CoV-2; SARS-CoV-2 - drug effects; Transcriptome; Viral Load; aberrant neutrophils; Paquinimod; S100A8/A9; SARS-CoV-2
• ISSN: 1931-3128; 1934-6069; 1934-6069
• DOI: 10.1016/j.chom.2020.12.016

The severe acute respiratory syndrome coronavirus 2 (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 was dramatically induced by coronavirus infection. Paquinimod treatment could reduce these neutrophils and regain anti-viral responses, unveiling key roles of S100A8/A9 and aberrant neutrophils in the pathogenesis of COVID-19, highlighting new opportunities for therapeutic intervention. [Display omitted] •S100A8 is dramatically upregulated in SARS-CoV-2-infected animal models and patients•A group of aberrant immature neutrophils is induced during SARS-CoV-2 infection•Immune disorder is mediated by the S100A8/A9-TLR4 pathway•S100A8/A9 inhibitor, Paquinimod, could prevent COVID-19-associated immune disorder Guo et al. demonstrate that over-activation of S100A8/A9-TLR4 signaling results in immune imbalance and expansion of aberrant immature neutrophils during SARS-CoV-2 infection. Relevant therapeutic targets were validated in animal infection models.