SARS-CoV-2 spike protein removes lipids from model membranes and interferes with the capacity of high density lipoprotein to exchange lipids

Abstract

Cholesterol has been shown to affect the extent of coronavirus binding and fusion to cellular membranes. The severity of Covid-19 infection is also known to be correlated with lipid disorders. Furthermore, the levels of both serum cholesterol and high-density lipoprotein (HDL) decreases with Covid-19 severity, with normal levels resuming once the infection has passed. Here we demonstrate that the SARS-CoV-2 spike (S) protein interferes with the function of lipoproteins, and that this is dependent on cholesterol. In particular, the ability of HDL to exchange lipids from model cellular membranes is altered when co-incubated with the spike protein. Additionally, the S protein removes lipids and cholesterol from model membranes. We propose that the S protein affects HDL function by removing lipids from it and remodeling its composition.

Progressive membrane-binding mechanism of SARS-CoV-2 variant spike proteins

“…There are hints of specific lipids being recognized by spike proteins. Candidates involved in SARS-CoV-2 spike binding and viral entry include phosphatidylcholine, phosphatidylserine (Asandei et al, 2020;Luchini et al, 2021), phosphatidylinositol 3,5-bisphosphate (PtdIns (3,5)P 2 ) (Kang et al, 2020;Ou et al, 2020), and cholesterol (Correa et al, 2021;Wei et al, 2020), which is known to be important for COVID-19 disease progression (Sanders et al, 2021). Spikes are also observed to co-locate with PtdIns(4,5)P 2 in the plasma membrane (Raut et al, 2022).…”

Coronavirus Infection and Cholesterol Metabolism

“…In particular, decreased serum HDL-C levels are positively correlated with COVID-19 infection severity ( 239 ). As infection worsens, serum TC and HDL are lowered, but upon recovery, cholesterol levels return to normal ( 65 , 239 – 243 ). This may be due to SARS-CoV-2 S proteins affecting HDL functions by removing lipids from HDL and remodeling its composition/structure ( 243 ), potentially affecting virus clearance in infected patients ( 244 ).…”

“…As infection worsens, serum TC and HDL are lowered, but upon recovery, cholesterol levels return to normal ( 65 , 239 – 243 ). This may be due to SARS-CoV-2 S proteins affecting HDL functions by removing lipids from HDL and remodeling its composition/structure ( 243 ), potentially affecting virus clearance in infected patients ( 244 ). Thus, serum cholesterol and lipoprotein marker monitoring may have an important clinical value for COVID-19 risk prediction ( 115 ).…”

Good Cholesterol Gone Bad? HDL and COVID-19

“…This stems from HDL's anti-inflammatory, anti-oxidative, and antiapoptotic effects, possibly reflecting the roles of specific sub-species of HDL particles, resulting in the activation of signaling pathways stemming from their interaction with SR-B1 and HDL-bound S1P-activating S1PRs [137,[204][205][206]. The SARS-CoV-2 spike protein is known to interact with HDL, at least in vitro, by virtue of its ability to bind cholesterol [26,207]. If it similarly interacts with HDL in vivo, then this may further contribute to the alterations in HDL structure and function, impacting HDL's ability to elicit protective signaling in endothelial and other cell types, preventing normal HDL-mediated protective pathways, and rendering cells susceptible to processes triggering inflammation and dysfunction.…”