The role of high cholesterol in age-related COVID19 lethality.

BioRxiv : the Preprint Server for Biology
Hao WangScott B Hansen

Abstract

Coronavirus disease 2019 (COVID19) is a respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originating in Wuhan, China in 2019. The disease is notably severe in elderly and those with underlying chronic conditions. A molecular mechanism that explains why the elderly are vulnerable and why children are resistant is largely unknown. Here we show loading cells with cholesterol from blood serum using the cholesterol transport protein apolipoprotein E (apoE) enhances the entry of pseudotyped SARS-CoV-2 and the infectivity of the virion. Super resolution imaging of the SARS-CoV-2 entry point with high cholesterol shows almost twice the total number of endocytic entry points. Cholesterol concomitantly traffics angiotensinogen converting enzyme (ACE2) to the endocytic entry site where SARS-CoV-2 presumably docks to efficiently exploit entry into the cell. Furthermore, in cells producing virus, cholesterol optimally positions furin for priming SARS-CoV-2, producing a more infectious virion with improved binding to the ACE2 receptor. In vivo, age and high fat diet induces cholesterol loading by up to 40% and trafficking of ACE2 to endocytic entry sites in lung tissue from mice. We propose a compo...Continue Reading

Citations

Sep 5, 2020·Signal Transduction and Targeted Therapy·Wonhwa LeeYoung-Kyo Seo
Jul 9, 2020·Journal of Clinical Medicine·Mattia VinciguerraErnesto Greco
Aug 6, 2020·International Journal of Molecular Sciences·Daniel Lietha, Tina Izard
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Jan 16, 2021·Irish Journal of Medical Science·Arsalan SalariZahra Ahmadnia
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Feb 13, 2021·Nature Communications·Yunkai ZhuRong Zhang
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May 6, 2021·International Journal of Molecular Sciences·Anastasia V PoznyakAlexander N Orekhov
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Sep 10, 2021·Arteriosclerosis, Thrombosis, and Vascular Biology·Kun ZhangTie-Lin Yang

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Datasets Mentioned

BETA
ABD72995.1
QII57161.1

Methods Mentioned

BETA
transfection
Assay

Software Mentioned

GraphPad Prism
Statistical
Zen
dSTORM
Vutara SRX

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