Cholesterol-Rich Lipid Rafts as Platforms for SARS-CoV-2 Entry

Abstract

Since its appearance, the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), the causal agent of Coronavirus Disease 2019 (COVID-19), represents a global problem for human health that involves the host lipid homeostasis. Regarding, lipid rafts are functional membrane microdomains with highly and tightly packed lipid molecules. These regions enriched in sphingolipids and cholesterol recruit and concentrate several receptors and molecules involved in pathogen recognition and cellular signaling. Cholesterol-rich lipid rafts have multiple functions for viral replication; however, their role in SARS-CoV-2 infection remains unclear. In this review, we discussed the novel evidence on the cholesterol-rich lipid rafts as a platform for SARS-CoV-2 entry, where receptors such as the angiotensin-converting enzyme-2 (ACE-2), heparan sulfate proteoglycans (HSPGs), human Toll-like receptors (TLRs), transmembrane serine proteases (TMPRSS), CD-147 and HDL-scavenger receptor B type 1 (SR-B1) are recruited for their interaction with the viral spike protein. FDA-approved drugs such as statins, metformin, hydroxychloroquine, and cyclodextrins (methyl-β-cyclodextrin) can disrupt cholesterol-rich lipid rafts to regulate key molecules in the immune signaling pathways triggered by SARS-CoV-2 infection. Taken together, better knowledge on cholesterol-rich lipid rafts in the SARS-CoV-2-host interactions will provide valuable insights into pathogenesis and the identification of novel therapeutic targets.

SARS-CoV-2 Employ BSG/CD147 and ACE2 Receptors to Directly Infect Human Induced Pluripotent Stem Cell-Derived Kidney Podocytes

“…Although mature CTSL protein is present in podocytes, Calu-3 and glomerular endothelia cells, pro-CTSL is present in all the cell types which may explain the presence of the CTSL mRNA in all the cell types even when they do not express mature CTSL protein. It has been suggested that SARS-CoV-2 entry into host cells depends on the presence of cholesterol-rich lipid rafts, which facilitates membrane fusion through proteases such as TMPRSS2 or endosomal pathway using Cathepsin B&L ( Palacios-Rápalo et al, 2021 ). Our results suggests low levels of TMPRSS2 expression in podocyte, and we speculate that the use of BSG/CD147 as a receptor and CTSL as a processing enzyme for viral entry mediated by S protein might be a preferred mechanism for the podocytes.…”

Simvastatin Downregulates the SARS-CoV-2-Induced Inflammatory Response and Impairs Viral Infection Through Disruption of Lipid Rafts

“…Moreover, other raft-resident lipids such as sphingolipids and ceramides were seen as important in the mechanisms of fusion and virus entry into the cell, highlighting the importance of the integrity of lipid rafts in these mechanisms (42). In this context, the pharmacological redistribution of cholesterol and impaired lipid raft formation hampers the SARS-CoV-2 SARS-CoV-2 entry, and consequently the virus replication (34,(43)(44)(45). In line with the results obtained here with simvastatin pretreatment, other drugs that affect not only the synthesis but also the traffic of cholesterol through the endosomal pathway, such as itraconazole, fluoxetine and amitriptyline showed promising results as adjuvant therapy for COVID-19 (42,46,47).…”

SARS-CoV-2 pseudovirus enters the host cells through spike protein-CD147 in an Arf6-dependent manner

“…Therefore, the caveolar/lipid raft and cytoskeleton system may involve or assist in the entry process of SARS-CoV-2 pseudovirus. Lipid rafts enriched in sphingolipids and cholesterol are functional membrane microdomains, which provide a platform to allow receptors such as ACE2, CD147, and TMPRSS2 to be recruited for binding to the viral spike protein [ 31–34 ]. A cytoskeleton is composed of three major types of cytoskeletal polymers including actin filaments, microtubules, and intermediate filaments [ 35 ].…”