ABSTRACT
Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)-induced cytokine storms constitute the primary cause of coronavirus disease 19(COVID-19)progression,severity,criticality,and death.Gluco-corticoid and anti-cytokine therapies are frequently administered to treat COVID-19,but have limited clinical efficacy in severe and critical cases.Nevertheless,the weaknesses of these treatment modalities have prompted the development of anti-inflammatory therapy against this infection.We found that the broad-spectrum anti-inflammatory agent inosine downregulated proinflammatory interleukin(IL)-6,upregulated anti-inflammatory IL-10,and ameliorated acute inflammatory lung injury caused by mul-tiple infectious agents.Inosine significantly improved survival in mice infected with SARS-CoV-2.It indirectly impeded TANK-binding kinase 1(TBK1)phosphorylation by binding stimulator of interferon genes(STING)and glycogen synthase kinase-3β(GSK3β),inhibited the activation and nuclear trans-location of the downstream transcription factors interferon regulatory factor(IRF3)and nuclear factor kappa B(NF-κB),and downregulated IL-6 in the sera and lung tissues of mice infected with lipopoly-saccharide(LPS),H1N1,or SARS-CoV-2.Thus,inosine administration is feasible for clinical anti-inflammatory therapy against severe and critical COVID-19.Moreover,targeting TBK1 is a promising strategy for inhibiting cytokine storms and mitigating acute inflammatory lung injury induced by SARS-CoV-2 and other infectious agents.