PT  - JOURNAL ARTICLE
AU  - Hao Wang
AU  - Zixuan Yuan
AU  - Mahmud Arif Pavel
AU  - Scott B. Hansen
TI  - The role of high cholesterol in age-related COVID19 lethality
AID  - 10.1101/2020.05.09.086249
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.09.086249
4099  - http://biorxiv.org/content/early/2020/05/29/2020.05.09.086249.short
4100  - http://biorxiv.org/content/early/2020/05/29/2020.05.09.086249.full
AB  - 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. Understanding these differences is critical for safeguarding the vulnerable and guiding effective policy and treatments. Here we show loading cells with cholesterol from blood serum using the cholesterol transport protein apolipoprotein E (apoE) enhances the endocytic entry of pseudotyped SARS-CoV-2. Super resolution imaging of the SARS-CoV-2 entry point with high cholesterol showed almost twice the total number of viral entry points. The cholesterol concomitantly traffics angiotensinogen converting enzyme (ACE2) to the viral entry site where SARS-CoV-2 docks to properly exploit entry into the cell. Cholesterol also increased binding of SARS-CoV-2 receptor binding domains. In mouse lung we found age and high fat diet induced cholesterol loading into lung tissue by up to 40%. Based on these findings, we propose a cholesterol dependent model for COVID19 lethality in elderly and the chronically ill. As cholesterol increases with age and inflammation (e.g. obesity, smoking, and diabetes), the cell surface is coated with viral entry points, optimally assembled viral entry proteins, and optimal furin priming. Importantly our model suggests problems arise when cholesterol levels are high in the tissue, not the blood. In fact, rapidly dropping cholesterol in the blood may indicate severe loading of cholesterol in peripheral tissue and a dangerous situation for escalated SARS-CoV-2 infectivity. Molecules that remove cholesterol from tissue or disrupt ACE2 localization with viral entry points or furin localization for priming in the producer cells, likely reduce the severity of COVID19 in critically ill patients.Competing Interest StatementThe authors have declared no competing interest.