The innate immune response to viral infection needs to be tightly regulated to ensure effective pathogen clearance while avoiding excessive immune activation. During SARS-CoV-2 infection, however, the immune system often fails to elicit appropriate responses, resulting in cytokine-release syndrome in patients with COVID-19. In this study, we show that reduced expression of Regnase-1, an RNase that negatively regulates immune cell activation, confers resistance to infection with the mouse-adapted SARS-CoV-2 MA10 strain. In Regnase-1 + /– mice, altered neutrophil function contributed to the amelioration of MA10-induced pneumonia. Single-cell RNA sequencing of lung tissue during MA10 infection revealed four distinct neutrophil subsets, and among these, a subset characterized by an interferon-stimulated gene (ISG) signature was decreased in Regnase-1 + /– mice. Furthermore, Regnase-1 + /– neutrophils exhibited reduced ISG expression without corresponding changes in proinflammatory gene expression. Regnase-1 was found to repress the expression of Tsc22d3 , a gene involved in the negative regulation of interferon responses, through its 3′ untranslated region. Collectively, these findings suggest that Regnase-1 attenuates resistance to SARS-CoV-2 MA10 infection by promoting excessive interferon responses in neutrophils.
Yasuda et al. (Mon,) studied this question.