In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 19, No. 5 ( 2023-5-3), p. e1011323-
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 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 .
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1011323
DOI:
10.1371/journal.ppat.1011323.g001
DOI:
10.1371/journal.ppat.1011323.g002
DOI:
10.1371/journal.ppat.1011323.g003
DOI:
10.1371/journal.ppat.1011323.g004
DOI:
10.1371/journal.ppat.1011323.g005
DOI:
10.1371/journal.ppat.1011323.g006
DOI:
10.1371/journal.ppat.1011323.s001
DOI:
10.1371/journal.ppat.1011323.s002
DOI:
10.1371/journal.ppat.1011323.s003
DOI:
10.1371/journal.ppat.1011323.s004
DOI:
10.1371/journal.ppat.1011323.s005
DOI:
10.1371/journal.ppat.1011323.s006
DOI:
10.1371/journal.ppat.1011323.s007
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2205412-1
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