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.

In this paper the transcriptome of rhesus macaques and mice infected with SARS-CoV-2 was characterized. 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.