Cholesterol and COVID-19-therapeutic opportunities at the host/virus interface during cell entry

Abstract

The rapid development of vaccines to combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections has been critical to reduce the severity of COVID-19. However, the continuous emergence of new SARS-CoV-2 subtypes highlights the need to develop additional approaches that oppose viral infections. Targeting host factors that support virus entry, replication, and propagation provide opportunities to lower SARS-CoV-2 infection rates and improve COVID-19 outcome. This includes cellular cholesterol, which is critical for viral spike proteins to capture the host machinery for SARS-CoV-2 cell entry. Once endocytosed, exit of SARS-CoV-2 from the late endosomal/lysosomal compartment occurs in a cholesterol-sensitive manner. In addition, effective release of new viral particles also requires cholesterol. Hence, cholesterol-lowering statins, proprotein convertase subtilisin/kexin type 9 antibodies, and ezetimibe have revealed potential to protect against COVID-19. In addition, pharmacological inhibition of cholesterol exiting late endosomes/lysosomes identified drug candidates, including antifungals, to block SARS-CoV-2 infection. This review describes the multiple roles of cholesterol at the cell surface and endolysosomes for SARS-CoV-2 entry and the potential of drugs targeting cholesterol homeostasis to reduce SARS-CoV-2 infectivity and COVID-19 disease severity.

Figure 1.. Cholesterol at the cell surface influences SARS-CoV-2 cell entry.

(i) Cholesterol depletion displaces ACE2 from rafts and reduces SARS-CoV-2 docking and ACE2-dependent viral envelope fusion with the host membrane as well as endocytotic virus uptake. Spike protein oligomerization improves viral membrane fusion and is enhanced by cholesterol. (ii) Cholesterol loading of cells induces CD147 levels, which can mediate SARS-CoV-2 endocytosis and contribute to the higher risk for severe COVID-19 in dyslipidemia. (iii) ADAM10/17 contribute to S protein processing and are activated in cholesterol-depleted cells, a route that may overcome reduced infection efficacy when cell surface cholesterol levels are low. Abbreviations: ADAM 10/17, A Disintegrin And Metalloproteinase 10/17; ACE2, angiotensin-converting enzyme 2; CD147, cluster of differentiation 147; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; S protein, spike protein.

Figure 2.. Effect of statins on SARS-CoV-2 infection.

Statin-induced ACE2 displacement from cholesterol-rich lipid rafts and lowering of CD147 plasma membrane levels interfere with viral fusion and/or viral entry via endocytosis. Statins prevent ACE2 down-regulation upon SARS-CoV-2 infection and inhibit NF-kB and TLR4-regulated inflammatory pathways. Abbreviations: ACE2, angiotensin-converting enzyme 2; CD147, cluster of differentiation 147; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; S protein, spike protein; TLR4, Toll-like receptor 4.

Figure 3.. SREBP2 activation is related to inflammation in PBMCs of COVID-19 patients.

SCAP-mediated escort of SREBP2 from the ER to the Golgi apparatus is required for the translocation of NLRP3 to the Golgi, enabling formation and activation of the inflammasome. Abbreviations: NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3, NOD-, LRR-, and pyrin domain–containing protein 3; PBMCs, peripheral blood mononuclear cells; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SCAP, SREBP2 cleavage–activating protein; SREBP2, sterol regulatory element–binding protein 2.