Abstract
Coronavirus Disease 2019 (COVID-19) is predominantly a respiratory tract infection that significantly rewires the host metabolism. Here, we monitored a cohort of COVID-19 patients’ plasma lipidome over the disease course and identified triacylglycerol (TG) as the dominant lipid class present in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced metabolic dysregulation. In particular, we pinpointed the lipid droplet (LD)-formation enzyme diacylglycerol acyltransferase (DGAT) and the LD stabilizer adipocyte differentiation-related protein (ADRP) to be essential host factors for SARS-CoV-2 replication. Mechanistically, viral nucleo capsid protein drives DGAT1/2 gene expression to facilitate LD formation and associates with ADRP on the LD surface to complete the viral replication cycle. DGAT gene depletion reduces SARS-CoV-2 protein synthesis without compromising viral genome replication/transcription. Importantly, a cheap and orally available DGAT inhibitor, xanthohumol, was found to suppress SARS-CoV-2 replication and the associated pulmonary inflammation in a hamster model. Our findings not only uncovered the mechanistic role of SARS-CoV-2 nucleocapsid protein to exploit LDs-oriented network for heightened metabolic demand, but also the potential to target the LDs-synthetase DGAT and LDs-stabilizer ADRP for COVID-19 treatment.
Highlights
Introduction The collective scientific understanding ofCoronavirusDisease 2019 (COVID-19) has evolved rapidly since its emergence, from the recognition of the causative virus, evaluation of therapeutics, to the development of multiple candidate vaccines within the span of a year[1,2,3,4]
SARS-CoV-2 reprograms host TG metabolism upon infection To depict the lipidomic landscape after SARS-CoV-2 infection over time, we monitored the lipidome of a clinical cohort with serially collected plasma specimens at days 0, 3, and 7 after hospitalization from 11 RT-qPCRconfirmed COVID-19 patients (Supplementary Table S1)
Collectively, our findings confirm the massive engagement of host lipid droplet (LD)-networking upon SARS-CoV-2 infection and identified hitherto unrecognized roles of diacylglycerol acyltransferase (DGAT) and adipocyte differentiation-related protein (ADRP) during SARS-CoV-2 infection (Fig. 6)
Summary
Disease 2019 (COVID-19) has evolved rapidly since its emergence, from the recognition of the causative virus, evaluation of therapeutics, to the development of multiple candidate vaccines within the span of a year[1,2,3,4]. There remain many significant unanswered questions, especially with regard to the underlying molecular mechanisms associated with the metabolic alterations of COVID-195. It is still unclear what are the SARS-CoV-2. To fulfill the requirements of rapid and massive clonal replication, viruses must co-opt distinct host programs to meet heightened metabolic demands. We previously documented the essentiality of lipogenic reshaping in Middle East respiratory syndrome coronavirus (MERS-CoV) replication[6], which is another betacoronavirus that can cause life-threatening infections in humans. The precise mechanisms involved in these host–virus interactions remain largely mysterious
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