The role of high cholesterol in SARS-CoV-2 infectivity

Wang, Hao; Yuan, Zixuan; Pavel, Mahmud Arif; Jablonski, Sonia Mediouni; Jablonski, Joseph; Hobson, Robert J.; Valente, Susana T.; Reddy, Chakravarthy; Hansen, Scott B.

doi:10.1016/j.jbc.2023.104763

Cited by 23 publications

(14 citation statements)

References 71 publications

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“…Notably, dSTORM excels in revealing shear-induced shifts in spatial patterning 2,4,8–11 . We discovered that EGFP provides a convenient means of quantifying shear-induced alterations in lipid localization.…”

Section: Resultsmentioning

confidence: 99%

Super-resolution imaging of potassium channels with genetically encoded EGFP

Call,

Bois,

Hansen

2023

Preprint

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The plasma membrane is a well-organized structure of lipids and proteins, segmented into lipid compartments under 200 nm in size. This specific spatial patterning is crucial for the function of proteins and necessitates super-resolution imaging for its elucidation. Here, we establish that the genetically encoded enhanced green fluorescent protein (EGFP), when combined with direct optical reconstruction microscopy (dSTORM), tracks shear- and cholesterol-induced nanoscopic patterning of potassium channels overexpressed in HEK293T cells. Leveraging EGFP in dSTORM (EGFP-STORM), our findings indicate that cholesterol directs the C-terminus of TWIK-related potassium channel (TREK-1) to ceramide-enriched lipid ganglioside (GM1) clusters. In the absence of the C-terminus, the channel associates with phosphatidylinositol 4,5-bisphosphate (PIP2) cluster. Similarly, cholesterol derived from astrocytes repositions EGFP-tagged inward-rectifying potassium (Kir) channels into GM1 clusters. Without cholesterol, the channel aligns with PIP2 lipids. We deduce that cholesterolʼs interaction with Kir sequesters the channel, separating it from its activating lipid PIP2. Fundamentally, a genetically encoded EGFP tag should make any protein amenable to dSTORM analysis.

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Section: Resultsmentioning

confidence: 99%

Super-resolution imaging of potassium channels with genetically encoded EGFP

Call,

Bois,

Hansen

2023

Preprint

Self Cite

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“…Various human pathogenic viruses depend on the hosts’ lipid metabolism for infection and replication. Patients with severe infectious diseases have low levels of low-density lipoprotein (LDL) and high-density lipoprotein (HDL), and cholesterol loading of immune cells and most likely further cells and tissues seems to contribute to hypolipidemia ( Wang et al, 2023 ). Accordingly, serum lipoprotein levels have prognostic value to predict the severity and mortality of patients with COVID-19 ( Liu et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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

Grewal,

Nguyen,

Buechler

2024

Life Sci. Alliance

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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.

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“…[5] Moreover, a high level of cholesterol significantly increased mortality among COVID-19 patients. [6] Therefore, cholesterol serves as a critical indicator in clinical biochemistry, and the timely and accurate determination of an individual's blood cholesterol level holds significant importance for early disease diagnosis and prevention.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, recent research has shown that in survivors of COVID‐19 the levels of LDL cholesterol, triglycerides and total cholesterol were increased, and the levels of HDL cholesterol were decreased compared with control patients who had never had a positive COVID‐19 test [5] . Moreover, a high level of cholesterol significantly increased mortality among COVID‐19 patients [6] . Therefore, cholesterol serves as a critical indicator in clinical biochemistry, and the timely and accurate determination of an individual‘s blood cholesterol level holds significant importance for early disease diagnosis and prevention.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of (3‐Thienyl)‐Substituted 2,2’‐Bipyridines and Their Application as Activators of Platinum Electrode Catalytic Activity Towards Cholesterol Electrooxidation

Okhokhonin.,

Stepanova,

Tsmokaluk

et al. 2024

ChemistrySelect

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Several new derivatives of 2,2′‐bipyridines with a spacer group separated from the 2,2‐bipyridine fragment, namely, an ethynyl fragment, were obtained using the Sonagashira cross‐coupling reaction. The resulting derivatives were physically adsorbed on platinum electrode and were then used as activators of the catalytic activity of a platinum electrode in the reaction of cholesterol electrooxidation in an acetonitrile medium. Sensitivity, limit of detection and detectable concentration range were calculated, and the best results was established as 6.2±0.6 μA/mM, 0.08 mM and 0–0.3 mM, respectively. These results show that the prepared compounds adsorbed on platinum electrode are perspective systems for developing of new enzymeless cholesterol sensor based on them.

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The role of high cholesterol in SARS-CoV-2 infectivity

Cited by 23 publications

References 71 publications

Super-resolution imaging of potassium channels with genetically encoded EGFP

Super-resolution imaging of potassium channels with genetically encoded EGFP

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

Synthesis of (3‐Thienyl)‐Substituted 2,2’‐Bipyridines and Their Application as Activators of Platinum Electrode Catalytic Activity Towards Cholesterol Electrooxidation

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