Year: 2022
Type: preprint
Abstract: 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 have 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 entry and fusion independent of transmembrane protease serine 2 expression in multiple cell types. We also demonstrate a role for ACAT in regulating SARS-CoV-2 RNA replication in primary bronchial epithelial cells. Furthermore, Avasimibe boosts the expansion of functional SARS-CoV-2-specific T cells from the blood of patients sampled in the acute phase of infection. Thus, re-purposing of available ACAT inhibitors provides a compelling therapeutic strategy for the treatment of COVID-19 to achieve both antiviral and immunomodulatory effects.
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Wellcome Trust, UK Research and Innovation, GW Pharmaceuticals, Barts Charity, Cancer Research UK, National Institute for Health and Care Research, Imperial College London, Chinese Academy of Medical Sciences, University College London Hospitals NHS Foundation Trust, UK Coronavirus Immunology Consortium, Medical Research Council
Awards: G1084281444, G1316475389, G1646284886, Harnessing tissue-resident CD8 T cells to manipulate hepatic immunity, G2226201423, G2418605839, G3636392608, Defining the innate-like mucosal T cell response to bacterial infection in airways disease, G4546281314, G520856161, Discovering the role of mucosal associated invariant T cells in respiratory immunity., G5889345363, Harnessing tissue-resident CD8 T cells to manipulate hepatic immunity, G2P-UK; A National Virology Consortium to address phenotypic consequences of SARSCoV-2 genomic variation, G6466068816, G6489997700, G7024631218, G704132455, Defining the role of hypoxia inducible factors in viral replication and pathogenesis, G7989741873, Understanding host factors that regulate the hepatitis B viral epigenome, G821720983, Defining the role of hypoxia inducible factors in viral replication and pathogenesis, Defining the innate-like mucosal T cell response to bacterial infection in airways disease, G9000115202
OpenAlex ID: W4223425519