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An ACAT inhibitor suppresses SARS-CoV-2 replication and boosts antiviral T cell activity
Peter A C Wing1,2, Nathalie M Schmidt3, Rory Peters2
1Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, United Kingdom.
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.
Insights
Avasimibe, an Acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, blocks SARS-CoV-2 infection by disrupting viral attachment and replication. This drug also enhances T cell responses, offering a dual therapeutic strategy for COVID-19 treatment.
Area of Science:
- Virology
- Immunology
- Cholesterol Metabolism
Background:
- SARS-CoV-2 severity depends on viral replication and host immunity.
- Cholesterol metabolism influences both the SARS-CoV-2 life cycle and T cell function.
Purpose of the Study:
- To investigate the therapeutic potential of targeting Acyl-CoA:cholesterol acyltransferase (ACAT) in COVID-19.
- To determine if ACAT inhibition affects SARS-CoV-2 infection and host immune responses.
Main Methods:
- Utilized SARS-CoV-2 pseudoparticle infection models.
- Employed single-cell imaging of viral RNA replication complexes.
- Conducted genetic studies involving ACAT isoform silencing and overexpression.
- Assessed T cell expansion from patient blood samples.
Main Results:
- Avasimibe, an ACAT inhibitor, inhibited SARS-CoV-2 pseudoparticle infection.
- Avasimibe disrupted the association of ACE2 and GM1 lipid rafts, impairing viral attachment.
- Avasimibe limited the formation of viral RNA replication complexes.
- Avasimibe treatment boosted the expansion of functional SARS-CoV-2-specific T cells.
Conclusions:
- ACAT plays a critical role in SARS-CoV-2 infection.
- Repurposing ACAT inhibitors like Avasimibe is a promising therapeutic strategy for COVID-19.
- ACAT inhibitors offer combined antiviral and immunomodulatory benefits for treating COVID-19.
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