An ACAT inhibitor suppresses SARS-CoV-2 replication and boosts antiviral T cell activity.
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...
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| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-05-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1011323 |
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| author | Peter A C Wing Nathalie M Schmidt Rory Peters Maximilian Erdmann Rachel Brown Hao Wang Leo Swadling COVIDsortium Investigators Joseph Newman Nazia Thakur Kaho Shionoya Sophie B Morgan Timothy Sc Hinks Koichi Watashi Dalan Bailey Scott B Hansen Andrew D Davidson Mala K Maini Jane A McKeating |
| author_facet | Peter A C Wing Nathalie M Schmidt Rory Peters Maximilian Erdmann Rachel Brown Hao Wang Leo Swadling COVIDsortium Investigators Joseph Newman Nazia Thakur Kaho Shionoya Sophie B Morgan Timothy Sc Hinks Koichi Watashi Dalan Bailey Scott B Hansen Andrew D Davidson Mala K Maini Jane A McKeating |
| author_sort | Peter A C Wing |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e445203a65eb44e382330b64fd988f25 |
| institution | OA Journals |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2023-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-e445203a65eb44e382330b64fd988f252025-08-20T02:31:38ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742023-05-01195e101132310.1371/journal.ppat.1011323An ACAT inhibitor suppresses SARS-CoV-2 replication and boosts antiviral T cell activity.Peter A C WingNathalie M SchmidtRory PetersMaximilian ErdmannRachel BrownHao WangLeo SwadlingCOVIDsortium InvestigatorsJoseph NewmanNazia ThakurKaho ShionoyaSophie B MorganTimothy Sc HinksKoichi WatashiDalan BaileyScott B HansenAndrew D DavidsonMala K MainiJane A McKeatingThe 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.https://doi.org/10.1371/journal.ppat.1011323 |
| spellingShingle | Peter A C Wing Nathalie M Schmidt Rory Peters Maximilian Erdmann Rachel Brown Hao Wang Leo Swadling COVIDsortium Investigators Joseph Newman Nazia Thakur Kaho Shionoya Sophie B Morgan Timothy Sc Hinks Koichi Watashi Dalan Bailey Scott B Hansen Andrew D Davidson Mala K Maini Jane A McKeating An ACAT inhibitor suppresses SARS-CoV-2 replication and boosts antiviral T cell activity. PLoS Pathogens |
| title | An ACAT inhibitor suppresses SARS-CoV-2 replication and boosts antiviral T cell activity. |
| title_full | An ACAT inhibitor suppresses SARS-CoV-2 replication and boosts antiviral T cell activity. |
| title_fullStr | An ACAT inhibitor suppresses SARS-CoV-2 replication and boosts antiviral T cell activity. |
| title_full_unstemmed | An ACAT inhibitor suppresses SARS-CoV-2 replication and boosts antiviral T cell activity. |
| title_short | An ACAT inhibitor suppresses SARS-CoV-2 replication and boosts antiviral T cell activity. |
| title_sort | acat inhibitor suppresses sars cov 2 replication and boosts antiviral t cell activity |
| url | https://doi.org/10.1371/journal.ppat.1011323 |
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