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...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal article |
| Language: | English |
| Published: |
Public Library of Science
2023
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| _version_ | 1826312629612707840 |
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| author | Wing, PAC Schmidt, NM Peters, R Erdmann, M Brown, R Wang, H Swadling, L Newman, J Thakur, N Shionoya, K Morgan, SB Hinks, TSC Watashi, K Bailey, D Hansen, SB Davidson, AD Maini, MK McKeating, JA |
| author2 | COVIDsortium Investigators |
| author_facet | COVIDsortium Investigators Wing, PAC Schmidt, NM Peters, R Erdmann, M Brown, R Wang, H Swadling, L Newman, J Thakur, N Shionoya, K Morgan, SB Hinks, TSC Watashi, K Bailey, D Hansen, SB Davidson, AD Maini, MK McKeating, JA |
| author_sort | Wing, PAC |
| collection | OXFORD |
| 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.
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Trial registration: NCT04318314. |
| first_indexed | 2024-04-23T08:23:32Z |
| format | Journal article |
| id | oxford-uuid:20d281b7-586b-4054-a2b9-8f61136cbd31 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-04-23T08:23:32Z |
| publishDate | 2023 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:20d281b7-586b-4054-a2b9-8f61136cbd312024-04-11T15:07:36ZAn ACAT inhibitor suppresses SARS-CoV-2 replication and boosts antiviral T cell activityJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:20d281b7-586b-4054-a2b9-8f61136cbd31EnglishSymplectic ElementsPublic Library of Science2023Wing, PACSchmidt, NMPeters, RErdmann, MBrown, RWang, HSwadling, LNewman, JThakur, NShionoya, KMorgan, SBHinks, TSCWatashi, KBailey, DHansen, SBDavidson, ADMaini, MKMcKeating, JACOVIDsortium InvestigatorsThe 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. <br> Trial registration: NCT04318314. |
| spellingShingle | Wing, PAC Schmidt, NM Peters, R Erdmann, M Brown, R Wang, H Swadling, L Newman, J Thakur, N Shionoya, K Morgan, SB Hinks, TSC Watashi, K Bailey, D Hansen, SB Davidson, AD Maini, MK McKeating, JA An ACAT inhibitor suppresses SARS-CoV-2 replication and boosts antiviral T cell activity |
| 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 |
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