Therapeutic strategy targeting host lipolysis limits infection by SARS-CoV-2 and influenza A virus

The biosynthesis of host lipids and/or lipid droplets(LDs)has been studied extensively as a putative therapeutic target in diverse viral infections.However,directly targeting the LD lipolytic catabolism in virus-infected cells has not been widely investigated.Here,we show the linkage of the LD-associated lipase activation to the breakdown of LDs for the generation of free fatty acids(FFAs)at the late stage of diverse RNA viral infections,which represents a broad-spectrum antiviral target.Dysfunction of membrane transporter systems due to virus-induced cell injury results in intracellular malnutrition at the late stage of infection,thereby making the virus more dependent on the FFAs generated from LD storage for viral morphogenesis and as a source of energy.The replication of SARS-CoV-2 and influenza A virus(IAV),which is suppressed by the treatment with LD-associated lipases inhibitors,is rescued by supplementation with FFAs.The administration of lipase inhibitors,either individually or in a combination with virus-targeting drugs,protects mice from lethal IAV infection and mitigates severe lung lesions in SARS-CoV-2-infected hamsters.Moreover,the lipase inhibitors significantly reduce proinflammatory cytokine levels in the lungs of SARS-CoV-2-and IAV-challenged animals,a cause of a cytokine storm important for the critical infection or mortality of COVID-19 and IAV patients.In conclusion,the results reveal that lipase-mediated intracellular LD lipolysis is commonly exploited to facilitate RNA virus replication and furthermore suggest that pharmacological inhibitors of LD-associated lipases could be used to curb current COVID-19-and future pandemic outbreaks of potentially troublesome RNA virus infection in humans.