Induction of alarmin S100A8/A9 mediates activation of aberrant neutrophils in the pathogenesis of COVID-19.
Induction of alarmin S100A8/A9 mediates activation of aberrant neutrophils in the pathogenesis of COVID-19.
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DOI：
10.1016/j.chom.2020.12.016
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发表时间：
2021-02-10
影响因子：
30.3
通讯作者：
You F
中科院分区：
文献类型：
--
作者：
Guo Q;Zhao Y;Li J;Liu J;Yang X;Guo X;Kuang M;Xia H;Zhang Z;Cao L;Luo Y;Bao L;Wang X;Wei X;Deng W;Wang N;Chen L;Chen J;Zhu H;Gao R;Qin C;Wang X;You F
严重急性呼吸系统综合征冠状病毒2型（SARS-CoV-2）大流行造成了前所未有的公共卫生危机。有证据表明，SARS-CoV-2感染会导致免疫系统失调。然而，早期免疫反应的独特特征仍然难以捉摸。我们对感染SARS-CoV-2的恒河猴和小鼠的转录组进行了表征。Alarmin S100 A8在SARS-CoV-2感染的动物模型以及COVID-19患者中被稳健地诱导。Paquinimod是一种S100 A8/A9的特异性抑制剂，可以拯救SARS-CoV-2感染小鼠的肺炎，并显著降低病毒载量。值得注意的是，在使用小鼠肝炎病毒（MHV）的小鼠冠状病毒感染的致死模型中，帕喹莫德治疗导致几乎100%的存活。一组中性粒细胞导致了不受控制的病理损伤和COVID-19的发病，这是由冠状病毒感染显著诱导的。帕喹莫德治疗可以减少这些中性粒细胞并重新获得抗病毒应答，揭示了S100 A8/A9和异常中性粒细胞在COVID-19发病机制中的关键作用，突出了治疗干预的新机会。Guo等人证明S100 A8/A9-TLR 4信号的过度激活导致SARS-CoV-2感染期间免疫失衡和异常未成熟中性粒细胞的扩增。在动物感染模型中验证了相关治疗靶点。
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. 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.
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