The Relationship Between Cholesterol and COVID19

By Yishayahu Ben Shemuel

Background

The covid19 virus (hereafter referred to as corona) is a virus belonging to the beta-corona family that exploded in full force in 2020, bringing the world into a race against time to find a solution. I investigated the data that is published about the virus to see if there are any vulnerabilities in the method of infection and dissemination that can be compromised by today's measures.

In this article, I investigate if there is a harmful link between cholesterol and the corona virus. Also, whether this information can be leveraged to combat the virus'es ability to infect.

Raw Data

In this section I will refer to some of the data published so far, concerning this matter

   Age as a Risk Factor

An early study of segmenting the Chinese patient population shows that as the age increases, so does the risk of dying from the virus. [1] Also, it is shown in a more recent study by the US Center for Disease Control (CDC) that the adult population is at higher risk, especially from the age of 60 and up. Risk increases with age. [2]

   Gender as a Risk Factor

From the earliest figures, the rate of infection between men and women appears to be similar, but the mortality rate for men is about 1% higher than for women. [3][4]

   Hypertension as a Risk Factor

Data collected in China on background diseases of the cases ending in death, found that 23% of the patients had high blood pressure as a background disease. Another study found that approximately 30% of the cases ending in death had high blood pressure as a background condition.

In both these studies and another study, diabetes was also a significant risk factor. [5]

   ACE Blockers and ARB Drugs

In an article cited above that compiled the data from China, the author concluded by commenting that most of these patients (with high blood pressure or diabetes), are usually treated with ACE or ARB blockers drugs. However, information was lacking on the patients' drug treatment. Taking these drugs may increase the risk of contracting the corona virus. [5]

This footnote has caused a big storm in the US where many patients taking these drugs fear they are in an increased risk group.

In response, various cardiologists' associations have rushed to issue a statement stating that these drugs should not be stopped unless explicitly directed to do so by the physician. [6]

Not all professionals are at ease. In a comment by some doctors, it was stated that there is indeed a reasonable suspicion of linking ACE blockers to increased risk. One of the strongest evidences for this is The fact that patients suffering from corona virus have an elevated concentration of angiotensin-2 in their blood. [7]

In general, it is noted that the lungs are rich in ACE receptors due to the multiplicity of blood vessels. [8]

It has also been previously known that one of the side effects of ACE blockers is dry cough. [9]

How the Virus Infiltrates a Cell

The virus envelope has a spike (called protein S) that attaches to the receptors in the animal cell. This attachment process activates a chain of responses that allows the virus to enter the cell.

Another virus from the Corona virus family, MHV, was found to penetrate the cell in two possible ways, either through fusion with the membrane or through endocytosis. [10]

The SARS virus also has an S protein that consists of two parts S1 and S2. The S1 part binds to receptors while the S2 part allows fusion of the virus membrane with the host cell membrane. [11]

This means that at every stage of the virus infiltration there is a critical stage of membrane fusion (as opposed to, for example, the production of a porin through which genetic material is poured).

The Relationship Between Cholesterol and The Infection and Spread of the Virus

One of the known functions of cholesterol in the cells is to regulate membrane fluidity so that it is not too fluid and; to prevent membrane freezing. [12] The Cholesterol does this by making Chemical bond with the phospholipids, while its size and rigidity prevent the compression of the phospholipids into compressed packaging. Note: The relationship between cholesterol and membrane fluidity is a topic that has been investigated a lot. Therefore, the relevant data as to the influence of the cholesterol on the membrane should be considered appropriately in context to viral penetration into the cell.

Arguably, the link between cholesterol and the virus is that the virus utilizes some carrier of LDL to infiltrate the cells as is found in other viruses such as the rhinovirus [13]. However, there is currently a broad agreement that the corona virus is aided by the ACE2 receptor [14], as is the case with other SARS viruses [13].

Why Cholesterol Is Related to The Process of Infection and Dissemination?

In 1991, a study was conducted on cells examining the effect of membrane cholesterol content on the fusion ability of mouse hepatitis virus (MHV) with the cell membrane. This virus also belongs to the beta-corona virus family and clearly showed increased fusion ability in the presence of cholesterol in the cell membrane. [15] This is not a pioneering study in the field. Such a study was already preceded by at least one study with similar results. [16]

Experiments With Viruses From Different Families

A study in 2004 found that cholesterol facilitates the fusion process of MHV virus with the cells. [17] Although, in this study, other hypotheses have been made regarding the association between cholesterol and the fusion process.

A study in 2018, of Flavivirus (a non-corona virus) found that cholesterol was linked to the virus'es proliferative potential. Although, the hypothesis is that LDL has a different role in the viral cycle and that it helps build the replicative complexes. Likewise, the virus infiltrates into the cells with the aid of the LDL receptors. At the end of the paper, (my) recommendations for using cholesterol-lowering drugs are made because they lower the amount of cholesterol available for the virus and, they effect immune system activation. [18] It is worth noting that in another study, low cholesterol was also associated with patients' immune response. [19]

The study of influenza viruses has also shown links between cholesterol content and the fusion ability of the virus with the membrane. [20] This study endeavored to show that it is actually the membrane cholesterol content and not the overall cholesterol content in the cell that is relevant to increased viral penetration.

Dengue virus (that causes the dengue fever illness) also belongs to the Flavivirus virus family. In A study conducted on this virus it was shown that soon after infection there is an increase in the amount of cholesterol produced. This too also raises the suspicion that the membrane cholesterol allows for a better connection for the fusion of the virus with the membrane. [21]

The HCV-causing hepatitis virus has been found that high cholesterol content in the membrane allows a better link of the virus to the membrane, thereby permitting its entry into the cell. When there is a low cholesterol content then, the virus is less likely to bind and penetrate the cell membrane. [22]

All of the above shows that there is ample evidence to support the idea that with different viruses; cholesterol has a critical effect on the virus's ability to infect and thrive. 

There can be a number of reasons for this:

1. Cholesterol is required for the virus different synthesis processes

2. Membrane cholesterol is an anchor with which the virus binds to the membrane

3. High membrane cholesterol content allows for an easier fusion process

By the way, I would like to point out that for these reasons, it seems understandable that cells have a mechanism that detects a sharp decrease in cholesterol content which activates the immune system.

Since experiments with the MHV virus which is relatively close to the covid19 virus have shown that the MHV virus presents a shorter time for fusion with cells that have a high content of membrane cholesterol. So too, it can be hypothesized that the covid19 virus is also more likely to infect cells with high cholesterol in the membrane.

Even if the cause is different, it seems that lowering the amount of cholesterol will help fight the virus, as it prevents the virus'es proliferation, as it also may help to activate the immune system at an early stage.

Recommendation: How to Lower Cholesterol in The Influenza Virus

Already, there are studies that recommend the treatment of cholesterol-lowering drugs as a means of treatment for patients with influenza virus. [23][24]

How Is All The Data Already Collected on COVID19 is Related?

1. The figure showing that there is a decrease in LDL among (covid19) patients begs for an explanation. [25] The explanation for this could be due to a massive use of the cholesterol by the virus or; due to immune system reactions or; both. In any case, it should be noted that there is a decrease in the cholesterol content, not just the LDL.

2. In general, women before menopausal stage have less LDL. Also, it is known that average cholesterol levels in the blood rises with age. [26]

3. There is a significant correlation between high blood pressure and high cholesterol levels that is expressed by high levels of LDL. [27]

4. Of the lipoproteins, LDL contains the highest amount of cholesterol. [28]

Combining all the data facilitates the assumption that cholesterol and LDL play a major role in increasing the risk of contracting the virus.

Before summarizing, I want to discuss the high blood pressure medications mentioned above.

1. At the moment, ACE blocker medications require more in-depth testing due to the suspicion that they may increase the risk of contracting the corona virus. The proposed risk-enhancing mechanism is that these drugs cause increased production of ACE receptors, which facilitates the absorption of the virus into the host cell, as it is aided by these receptors.

2. Similar drugs, from the ARB family, can also cause similar affects to the ACE-blocking drugs. however, I think that they should be considered as additional risks. Their risk is that these drugs impair membrane thickness. (See [29] - a study supporting this conclusion.) This means that cell membranes are more permeable and less rigid. Either condition will allow for faster infection of the virus.

How to Use This Knowledge to Confront the Corona Epidemic

I would like to offer some suggestions to leverage this knowledge about the relationship between cholesterol and viral morbidity to help deal with the epidemic.

Each verified patient should undergo a blood test to check their blood LDL levels for risk assessment as well as control and research needs

Authenticated patients should receive statin treatment immediately in order to reduce recovery and infectious state and time

Individuals that have come in contact with infected individuals and at-risk patients should be given statins as a preventative measure so that the virus does not get absorbed. In addition, if the virus does get into the cells, its spread will be slowed by the administration of statins.

Consider using statins as a prophylactic treatment in communities where there is mass infection.

Patients who have recovered should also be administered blood tests to check their LDL levels for further research and control.

The link between high cholesterol and the chance of getting infections is known. Also, statins are currently recommended for treating viral infections. [23] [24] Therefore, I suggest considering using statins as a cholesterol-lowering drug (during this epidemic to prevent infection).

Incidentally, the FDA recently approved another cholesterol-lowering drug that works a little differently than the statin's. The approved drug is called Nexletol. Its antiviral effects may be considered in the near future.

Summary

Cholesterol appears to help the corona virus to proliferate and thrive. This is probably through assistance with the fusion process. But, there may be other reasons why cholesterol seems to help the virus spread. Preventing the viral use of cholesterol as a precursor to spreading, will reduce the virus'es ability to spread.

Because the main carrier of cholesterol is the blood-borne LDL, it must be reduced drastically to prevent the spread of the virus.

Given the above and the fact that statin drugs are relatively safe, especially when administered for a relatively short period, as well as inexpensive and readily available, their wide use in treating the corona virus should be seriously considered.

Verifying the information and hypothesis in this article will reduce the number of patients and carriers, which in turn will decrease the number of future patients. This will enable the health care system to focus on and provide relief in more difficult cases, where more extensive care is needed by precluding care for lessor cases.

Bibliography

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Biography: Yishayahu Ben Shemuel is an IDF army medic, pre-med and biology major student in Open University, Israel.

Givon Zirkind provided translation assistance.