ORIGINAL RESEARCH article
Front. Microbiol.
Sec. Virology
Volume 16 - 2025 | doi: 10.3389/fmicb.2025.1670356
Cholesterol in Viral Envelope Determines Infectivity of SARS-CoV-2 and Other Coronaviruses
Provisionally accepted
- Zhejiang Chinese Medical University, Hangzhou, China
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The SARS-CoV-2 pandemic had unprecedented impacts on public health and the economy. Many studies have focused on the mechanisms of SARS-CoV-2 entry into host cells, particularly the spike (S) protein mediated receptor engagement and subsequent virus-host membrane fusion dynamics. However, the mechanistic contribution of cholesterol within spike-incorporated viral envelopes to infectivity has not been well characterized. Herein, we show that targeted cholesterol depletion from the viral envelopes of SARS-CoV-2, SARS-CoV, and MERS-CoV directly impaired viral infectivity in a dose-dependent manner. Although modulation of host cell membrane cholesterol exerted relatively minor effects on viral entry, host cellular cholesterol homeostasis critically governs progeny virion infectivity by determining cholesterol content within nascent viral envelopes. Virions derived from cells with reduced plasma membrane cholesterol demonstrate significantly attenuated infectivity in SARS-CoV-2 and related coronaviruses. In addition, we detected that exogenous cholesterol replenishment restored SARS-CoV-2 entry efficiency by augmenting virus attachment. Collectively, our data demonstrate that biophysical properties of human coronavirus envelopes, particularly cholesterol stoichiometry, function as a key molecular determinant regulating host cell susceptibility. These findings position viral lipidome remodeling as a viable therapeutic target for developing host-directed broad-spectrum antivirals.
Keywords: Human coronaviruses, Viral envelope cholesterol, Entry efficiency, Viral attachment, Therapeutic target
Received: 21 Jul 2025; Accepted: 08 Sep 2025.
Copyright: © 2025 Xu, Wang, Zhang, Jin, Tan, Huang, Zhou and Wen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Xiaoying Xu, Zhejiang Chinese Medical University, Hangzhou, China
Lin Huang, Zhejiang Chinese Medical University, Hangzhou, China
Mingqian Zhou, Zhejiang Chinese Medical University, Hangzhou, China
Chengping Wen, Zhejiang Chinese Medical University, Hangzhou, China
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