부산대학교 도서관

The severity of disease following infection with SARS-CoV-2 is determined by viral replication kinetics and host immunity, with early T cell responses and/or suppression of viraemia driving a favourable outcome. Recent studies uncovered a role for cholesterol metabolism in the SARS-CoV-2 life cycle and in T cell function. Here we show that blockade of the enzyme Acyl-CoA:cholesterol acyltransferase (ACAT) with Avasimibe inhibits SARS-CoV-2 pseudoparticle infection and disrupts the association of ACE2 and GM1 lipid rafts on the cell membrane, perturbing viral attachment. Imaging SARS-CoV-2 RNAs at the single cell level using a viral replicon model identifies the capacity of Avasimibe to limit the establishment of replication complexes required for RNA replication. Genetic studies to transiently silence or overexpress ACAT isoforms confirmed a role for ACAT in SARS-CoV-2 infection. Furthermore, Avasimibe boosts the expansion of functional SARS-CoV-2-specific T cells from the blood of patients sampled during the acute phase of infection. Thus, re-purposing of ACAT inhibitors provides a compelling therapeutic strategy for the treatment of COVID-19 to achieve both antiviral and immunomodulatory effects. Trial registration: NCT04318314. Author summary: Cholesterol metabolism is a key element in both viral replication and immune cell signalling. We show that Avasimibe, an inhibitor of the cholesterol esterification enzyme Acyl-CoA:cholesterol acyltransferase (ACAT), potently inhibits SARS-CoV-2 entry and viral RNA replication. Importantly, Avasimibe boosts the expansion of functional SARS-CoV-2-specific T cells isolated from the blood of patients sampled during the acute phase of infection. Our findings show that Avasimibe has combined antiviral and T cell boosting properties in acute SARS-CoV-2 infection. This study reinforces an emerging picture of the importance of cholesterol metabolism in viral replication and T cell immunity, providing new insights on intrinsic anti-viral pathways that may be applicable to other viral pathogens. [ABSTRACT FROM AUTHOR]