The dysregulated immune response and inflammation resulting in severe COVID-19 are still incompletely understood. Having recently determined that aberrant death-ligand-induced cell death can cause lethal inflammation, we hypothesized that this process might also cause or contribute to inflammatory disease and lung failure following SARS-CoV-2 infection. To test this hypothesis, we developed a novel mouse-adapted SARS-CoV-2 model (MA20) that recapitulates key pathological features of COVID-19. Concomitantly with occurrence of cell death and inflammation, FasL expression was significantly increased on inflammatory monocytic macrophages and NK cells in the lungs of MA20-infected mice. Importantly, therapeutic FasL inhibition markedly increased survival of both, young and old MA20-infected mice coincident with substantially reduced cell death and inflammation in their lungs. Intriguingly, FasL was also increased in the bronchoalveolar lavage fluid of critically-ill COVID-19 patients. Together, these results identify FasL as a crucial host factor driving the immuno-pathology that underlies COVID-19 severity and lethality, and imply that patients with severe COVID-19 may significantly benefit from therapeutic inhibition of FasL.

导致严重 COVID-19 的免疫反应失调和炎症尚不完全清楚。最近确定异常死亡配体诱导的细胞死亡可引起致命的炎症，我们假设这一过程也可能导致或促成 SARS-CoV-2 感染后的炎症性疾病和肺衰竭。为了检验这一假设，我们开发了一种新型的小鼠适应 SARS-CoV-2 模型 (MA20)，它概括了 COVID-19 的关键病理特征。随着细胞死亡和炎症的发生，MA20感染小鼠肺部炎症单核巨噬细胞和NK细胞中FasL的表达显着增加。重要的是，治疗性 FasL 抑制显着增加了年轻和年老 MA20 感染小鼠的存活率，同时大幅减少了肺部细胞死亡和炎症。有趣的是，重症 COVID-19 患者的支气管肺泡灌洗液中的 FasL 也有所增加。总之，这些结果表明 FasL 是驱动导致 COVID-19 严重性和致死性的免疫病理学的关键宿主因素，并意味着重症 COVID-19 患者可能会从 FasL 的治疗抑制中显着受益。