Is there a link between cholesterol and COVID-19?

The coronavirus is particularly devastating and deadly in the elderly and especially in those with co-morbidities such as heart disease, hypertension or diabetes. As indicated in the table below (New York City data) most of the deaths due to coronavirus occurs in people over 65 years of age accounting to nearly 75% of deaths.

One small silver lining in this entire global pandemic, is that children are either mostly asymptomatic or show very mild symptoms. I call it a silver lining because, let’s face it children are not the best at maintaining social distancing or at hand washing or covering their mouths when they cough or sneeze. All these features would have made the outbreak so much harder to control.

Interestingly, during the previous SARS outbreak in 2002-2003 (which killed 774 people and infected more than 8,000) a similar trend was observed where no deaths were observed in children 12 years and younger. Children somehow seemed to have been protected. There were only 80 laboratory-confirmed cases and 55 probable or suspected cases of SARS in children. Scientists still don’t understand the reason for this disparity in the lethality of the virus in adults’ vs kids.

Understanding the cause and mechanism of protection against viruses such as SARS in kids could possibly be the key to tackling not only the current pandemic, but also to prevent future outbreaks.

Age of Coronavirus Deaths

AGENumber of DeathsShare of deathsWith underlying conditionsWithout underlying conditionsUnknown if with underlying conditions.Share of deaths
of unknown + w/o conditions.
0 – 17 years old90.06%6300.02%
18 – 44 years old6013.9%476171080.8%
45 – 64 years old3,41322.4%2,851724903.7%
65 – 74 years old3,78824.9%2,80159826.5%
75+ years old7,41948.7%5,23622,18114.3%
TOTAL15,230100%11,370 (75%)99 (0.7%)1,551 (24.7%)25.3%
Source:  Data from New York City. New York City Health as of May 13, 2020:

How does the coronavirus enter the cell?

For over 100 years the scientific community hasn’t been able to come to a consensus to whether viruses are living or non-living.  One of the most fundamental requirements of a living organism is the ability to replicate. Viruses are microscopic infectious particles which can’t replicate on their own, but can definitely do so when they enter other living cells. Therefore, viruses are thought of as being in the gray area between living and nonliving. Can you believe something this tiny and not even alive on its own can cause such havoc?

File:3D medical animation coronavirus structure.jpg - Wikimedia ...
Picture courtesy: Wikimedia commons

In order to propagate, the virus needs to get hold of a living cell and get inside. For the coronavirus that process is initiated by the spike protein (S protein), which are the little protrusions sitting on the outside of the virus which happens to be the most popular photo around these days. The molecule (receptor) in the living cells which aids the viral entry is called angiotensin converting enzyme 2 (ACE2). Using the spike protein (key) the SARS-CoV2 virus binds to the ACE2 protein (lock) on the host cells sort of like a key being inserted into a lock which enables viral infection.  

What is ACE2?

ACE2 is expressed (or present) in the airways, lungs, heart, intestines, kidneys and blood vessels. ACE2 is a critical component of a system that regulates blood pressure, fluid, and mineral balance in the body.  ACE2 also plays an important role in wound healing and inflammation.

ACE2 appears to be the gateway for the entry of SARS-CoV2 into the body via the nostrils, mouth, lungs and other organs. Therefore, it seems logical to ask whether the quantity of this receptor in the body has anything to do with the severity of the disease in adults. If only science were that simple! Conflicting and often paradoxical data about the levels of ACE2 are arising from research around the world.  Initially, it was shown that the level of ACE2 is lowest in children which could explain their low rates of infection, and being mildly affected by the disease. However, more recent data indicates that the level of ACE2 is actually higher in children than in the adults. So this makes this story a bit more complicated.

Does cholesterol have a role in COVID-19 infection?

In a recent pre-print article published in bioRxiv, scientists from The Scripps Institute in Florida suggest that cholesterol might play a role in age related COVID-19 infectivity and severity. Cholesterol is found throughout the human body and is an important structural component of animal cell membranes. The accumulation of cholesterol in tissues however, increases with age and that of course causes a whole set of issues such as atherosclerosis, stroke etc but that will be another point of discussion. Let us now examine how cholesterol, age and COVID-19 are linked.

SARS-CoV viruses are known to enter the cells by employing lipid rafts and via a process of endocytosis. Lipid rafts are microdomains found on the membranes (outer surfaces) of cells and is made up of chemicals called cholesterol and sphingolipids.  These lipid rafts normally help in transporting substances required for normal cellular processes from the outside to the inside of the cells. Unfortunately, they can also act as sites of entry and assembly of pathogens such as the SARS-CoV viruses.

Scott.B Hansen and colleagues in this bioRxiv paper show that the entry of SARS-CoV2 depends on the presence of cholesterol. Further, in the presence of high levels of cholesterol, the virus entry points on the cell membrane are both markedly increased in size and number. And reducing the amount of cholesterol in the cells has the opposite effect. The authors therefore suggest that cholesterol might be a key player in age related lethality due to COVID-19. Cholesterol loading in cells significantly increases with aging and inflammation (caused by smoking, atherosclerosis and diabetes etc) making it conducive for the SARS-CoV2 virus to infect the cells in massive numbers causing significant damage in the elderly and people with co-morbidities.

Another interesting point is that high levels of cholesterol causes an increase in trafficking of the ACE2 receptor to the viral entry point and helps in the docking of the S-protein.

Cholesterol has been shown to be important for efficient replication (division and reproduction) of enteroviruses and the other SARS-CoV virus. Whether the same holds true for SARS-CoV2 is yet to be determined.

The bioRxiv, study proposes a new model for age related lethality due to COVID-19, mediated by cholesterol. However, there are a few caveats to consider.

1) The bioRxiv website said it has been “receiving many new papers on coronavirus SARS-CoV-2.” “These are preliminary reports that have not been peer-reviewed,” the website warns. “They should not be regarded as conclusive, guide clinical practice [or] health-related behavior, or be reported in news media as established information.” 

2) The experiments in this paper were done mainly in cell culture and not in animal models/humans. However, this does seem like a promising mechanism and could mean that there might be ways to look at treatment options for COVID-19, involving cholesterol lowering mechanisms.

3) Healthy diet and exercise are always good options for lowering cholesterol and could be the answer not only for this pandemic but for many other viral infections.

In summary, the novel coronavirus seems to be especially deadly in the old (>65 years old) and the vulnerable.  Smoking, hypertension (which is prevalent in people over 40) and diabetes may lead to increase in inflammation associated with an increase in cholesterol and this could be one of the reasons for worse outcomes in these patients due to COVID-19.

Currently, we are bang in the middle of this pandemic and we don’t have enough statistical evidence to make a direct correlation between cholesterol and death due to COVID-19. Once we are on the other side of this nightmare, there will be loads of demographic and statistical data which will help us better comprehend how each of these conditions (such as high cholesterol, smoking, hypertension, diabetes etc) relate to worsening of coronavirus prognosis.

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