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

Abstract

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.

Rewiring of the host cell metabolome and lipidome during lytic gammaherpesvirus infection is essential for infectious virus production

“…It is possible that SREBP1 contributes to the mechanism by which gammaherpesviruses induce lipogenesis, as we see a significant increase in numerous lipid species in our data. Finally, several RNA viruses also hijack host lipid metabolism, including Dengue virus, Hepatitis C virus, Influenza virus, and SARS-CoV-2 (44, 70, 71). Positive-single stranded RNA viruses enhance lipid droplet formation during early infection and hijack membranes during replication (72).…”

Photobiomodulation Reduces the Cytokine Storm Syndrome Associated with COVID-19 in the Zebrafish Model

“…Viruses, including coronaviruses, require lipid droplets (LDs) during their replication phase. LDs store mainly triacylglycerols utilized for membrane formation but also supply the cells with essential lipids for metabolic energy, signaling molecules, and inflammatory mediators, resulting in cytokine production [ 74 , 75 , 76 , 77 , 78 ]. Due to their importance for viral replication, LDs have been proposed as therapeutic targets against SARS-CoV-2 infection since interfering with lipid synthesis and storage would decrease the infection.…”

Solubilized curcuminoid complex prevents extensive immunosuppression through immune restoration and antioxidant activity: Therapeutic potential against SARS-CoV-2 (COVID-19)

“…85‐23, 1985, revised 1996). The strain of SARS-CoV-2, KCDC03 (isolated from a Korean COVID-19 patient in 2020 and belonging to the A lineage of early Chinese strains), was kindly provided by the Korea Disease Control and Prevention Agency (Cheongju, South Korea) and propagated in Vero E6 cells (ATCC, Manassas, VA, USA) as previously described [25] . For therapeutic effects of C—S/M against SARS-CoV-2-infected hamsters, virus alone-infected and C—S/M−treated groups ( n = 5/groups) were challenged once by intratracheal inoculation of 10 5 TCID 50 of SARS-CoV-2 in 100 μL PBS.…”

“…Whole lung tissues were sampled from hamsters in each group at 5 days post-infection, and the gross lung lesion surfaces were examined using the ImageJ software (National Institutes of Health, United States) after taking photographs of the dorsal and ventral lung surfaces. Also, virus growth in the lungs of the hamsters was evaluated as previously described [25] . Briefly, total RNA was extracted using the RNeasy kit (Qiagen, Hilden, Germany) in homogenized lung tissues, and cDNA was synthesized using the TOPscript™ cDNA Synthesis kit (Enzynomics, Daejeon, South Korea) according to the manufacturer’s instructions.…”