An ACAT inhibitor suppresses SARS-CoV-2 replication and boosts antiviral T cell activity.

Autor: Wing PAC; Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, United Kingdom.; Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Schmidt NM; Division of Infection and Immunity and Institute of Immunity and Transplantation, UCL, London, United Kingdom., Peters R; Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Erdmann M; School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom., Brown R; Division of Infection and Immunity and Institute of Immunity and Transplantation, UCL, London, United Kingdom.; UCL Queen Square Institute of Neurology, London, United Kingdom., Wang H; Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute, San Diego, California, United States of America.; Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, San Diego, California, United States of America., Swadling L; Division of Infection and Immunity and Institute of Immunity and Transplantation, UCL, London, United Kingdom., Newman J; The Pirbright Institute, Woking, United Kingdom., Thakur N; The Pirbright Institute, Woking, United Kingdom., Shionoya K; Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.; Department of Applied Biological Science, Tokyo University of Science, Noda, Japan.; Research Centre for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo, Japan., Morgan SB; Respiratory Medicine Unit and National Institute for Health Research Oxford Biomedical Research Centre, Nuffield Department of Medicine, Experimental Medicine, University of Oxford, Oxford, United Kingdom., Hinks TS; Respiratory Medicine Unit and National Institute for Health Research Oxford Biomedical Research Centre, Nuffield Department of Medicine, Experimental Medicine, University of Oxford, Oxford, United Kingdom., Watashi K; Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.; Department of Applied Biological Science, Tokyo University of Science, Noda, Japan.; Research Centre for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo, Japan., Bailey D; The Pirbright Institute, Woking, United Kingdom., Hansen SB; UCL Queen Square Institute of Neurology, London, United Kingdom., Davidson AD; School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom., Maini MK; Division of Infection and Immunity and Institute of Immunity and Transplantation, UCL, London, United Kingdom., McKeating JA; Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, United Kingdom.; Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2023 May 03; Vol. 19 (5), pp. e1011323. Date of Electronic Publication: 2023 May 03 (Print Publication: 2023).
DOI: 10.1371/journal.ppat.1011323
Abstrakt: 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.
Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: NMS, PACW, JAM and MKM hold an international patent entitled No.1917498.6 entitled “Treatment of Hepatitis B Virus (HBV) Infection” filed by applicant UCL Business Ltd and have received unrestricted project funding from Gilead Sciences to investigate effects of ACAT inhibitors in HBV infection.
(Copyright: © 2023 Wing et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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