An ACAT inhibitor suppresses SARS-CoV-2 replication and boosts antiviral T cell activity.
An ACAT inhibitor suppresses SARS-CoV-2 replication and boosts antiviral T cell activity.
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DOI：
10.1371/journal.ppat.1011323
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发表时间：
2023-05
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
感染SARS-CoV-2后疾病的严重程度由病毒复制动力学和宿主免疫决定，早期T细胞反应和/或病毒血症的抑制推动了有利的结果。最近的研究揭示了胆固醇代谢在SARS-CoV-2生命周期和T细胞功能中的作用。在这里，我们表明，用avasimibe阻断酰基辅酶A：胆固醇酰基转移酶(ACAT)可以抑制SARS-CoV-2伪粒子感染，并破坏ACE2和GM1脂筏在细胞膜上的结合，扰乱病毒的附着。使用病毒复制子模型在单细胞水平上对SARS-CoV-2RNA进行成像，确定avasimibe限制RNA复制所需复制复合体的建立的能力。暂时沉默或过度表达ACAT亚型的遗传学研究证实了ACAT在SARS-CoV-2感染中的作用。此外，avasimibe可促进从感染急性期采集的患者血液中扩增功能性SARS-CoV-2特异性T细胞。因此，ACAT抑制剂的再利用为新冠肺炎的治疗提供了一个引人注目的治疗策略，以达到抗病毒和免疫调节的效果。试用登记：NCT04318314。胆固醇代谢是病毒复制和免疫细胞信号传递的关键因素。我们发现Avasimibe，一种胆固醇酯化酶酰基-CoA：胆固醇酰基转移酶(ACAT)的抑制剂，有效地抑制SARS-CoV-2进入和病毒RNA复制。重要的是，avasimibe促进了从感染急性期采集的患者血液中分离出来的功能性SARS-CoV-2特异性T细胞的扩张。我们的研究结果表明，阿瓦西米在急性SARS-CoV-2感染中具有抗病毒和增强T细胞的双重作用。这项研究加强了胆固醇代谢在病毒复制和T细胞免疫中的重要性的新图景，为可能适用于其他病毒病原体的内在抗病毒途径提供了新的见解。
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. Cholesterol metabolism is a key element in both viral replication and immune cell signalling. We show that Avasimibe, an inhibitor of the cholesterol esterification enzyme Acyl-CoA:cholesterol acyltransferase (ACAT), potently inhibits SARS-CoV-2 entry and viral RNA replication. Importantly, Avasimibe boosts the expansion of functional SARS-CoV-2-specific T cells isolated from the blood of patients sampled during the acute phase of infection. Our findings show that Avasimibe has combined antiviral and T cell boosting properties in acute SARS-CoV-2 infection. This study reinforces an emerging picture of the importance of cholesterol metabolism in viral replication and T cell immunity, providing new insights on intrinsic anti-viral pathways that may be applicable to other viral pathogens.
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