Is there a link between cholesterol and COVID-19?

By Dr. Poonam Balaji

                The coronavirus SARS-CoV2 and its associated disease, COVID-19, is particularly devastating in the elderly. COVID-19 is especially deadly in those with other co-morbidities such as heart disease, hypertension or diabetes. As shown in the table below (New York City data) most of deaths due to COVID-19 happen in people over 65 years of age accounting for nearly 75% of deaths¹.

COVID-19 among young people

                A small silver lining, to the COVID-19 pandemic is that children are either mostly asymptomatic or show very mild symptoms. Children also do not easily maintain physical distance or naturally think about hand-washing. They are also still learning to cover their mouths when they cough or sneeze. Since children are in contact with older adults and rarely show symptoms the outbreak is much harder to control.

                Interestingly, during the previous  SARS outbreak in 2002-2003  (which killed 774 people and infected more than 8,000)² 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’ compared to kids.

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

Age of COVID-19 Deaths in NYC²

How does SARS-CoV2 enter the cell?

                  For over 100 years the scientific community hasn’t reached a consensus on whether viruses are living or non-living.  One of the most fundamental requirements of a living organism is the ability to reproduce. Viruses are microscopic infectious particles which can’t replicate on their own. They can replicate when they enter 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?

                  The process of viral replication begins with entry. For the coronavirus that process is initiated by the spike protein (S protein) which are the little protrusions sitting on the top of the virus. Unsurprisingly, the most popular photo around these days shows these protein protrusions. The protein (receptor) in living cells which aids the viral entry is called angiotensin converting enzyme 2 (ACE2). Binding of the spike protein (key) on the SARS-CoV2 virus to the ACE2 protein (lock) on the host cells, sort of like a key being inserted into a lock which enables viral infection by SARS-CoV1 ⁴ and SARS-CoV2 ⁵.

What is ACE-2?

                   ACE2 is expressed in the airways, lung, heart, intestines, kidneys and blood vessels. This enzyme is a critical component of a system that regulates blood pressure, fluid, and mineral balance in the body.  It 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! As data has continued to be generated, 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 infection⁶, and being mildly affected by the disease. However, more recent data published to the pre-print repository BioRxiv indicates that the level of ACE2 is actually higher in children than in the adults ⁷. So this makes this story a bit more complicated and forces us to look for better explanations.

Does cholesterol have a role in COVID-19 infection?

                   In a recent pre-print article in bioRxiv scientists from The Scripps Institute in Florida suggest that cholesterol might play a role in age related COVID-19 infectivity and severity⁸. 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 contributes to morbidities such as atherosclerosis, increased blood pressure, stroke etc. Is there a link between age, cholesterol and COVID-19?

                   Coronaviruses are known to enter the cells by employing lipid rafts and via a process of endocytosis ⁹. 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 cells¹⁰. They can also act as a site of entry and assembly of pathogens such as the SARS-CoV viruses.

                   Scott B. Hansen and colleagues show that 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.

cholesterol levels and life styles

                 Cholesterol loading in cells significantly increases with aging and inflammation caused by smoking, atherosclerosis, diabetes, and other co-morbidities. This makes it more likely that SARS-CoV2 will infect more cells and cause significant damage to tissues of the elderly and people with co-morbidities. The authors suggest that cholesterol might be a key player in age related lethality due to COVID-19.

                   Another interesting point is that high levels of cholesterol cause an increase in trafficking of the ACE2 receptor to the viral entry point although this point also remains controversial ¹¹. If ACE2 does traffic to lipid rafts it might increase docking of the S-protein. Cholesterol has also been shown to be important for efficient replication (division and reproduction) of enteroviruses and other the SARS-CoV virus. Whether the same holds true for SARS-CoV2 is yet to be determined.

Summary and recommendations

                  This study proposes a new model for age related lethality due to COVID-19 mediated by cholesterol. However there are a few caveats to consider. The bioRxiv website said it has been “receiving many new papers on coronavirus SARS-CoV-2.”Additionally they caution that “These are preliminary reports that have not been peer-reviewed,” and that “They should not be regarded as conclusive, guide clinical practice [or] health-related behavior, or be reported in news media as established information.” 

                  The experiments in this paper were done 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.

                  Healthy diet and exercise are encouraged to lower cholesterol and could play a role not only in SARS-CoV2 infection, but for many other viral infections.

                 In summary, COVID-19 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 correlate to worsening of coronavirus prognosis.

About Dr. Poonam Balaji:

                  I am a qualified scientist with a PhD in cardiovascular physiology and Molecular biology from The Ohio State University. I have over 15 years of experience in research and am passionate about everything science and medicine. Science communication is my new found interest. You can find more of my writing at https://cuppa.science.blog/.

References:

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