High cholesterol could be the culprit in coronavirus deaths
Cholesterol long has confounded medical science, given its important role in forming cell membranes, hormones and the sheaths that insulate nerves while also being responsible for such conditions as fatty liver disease and clogged arteries.
Now adding to those harms, a study by the Scripps Research Institute has shown high cholesterol levels in lung tissue may be the key culprit in COVID-19 deaths, especially for those with such underlying chronic conditions as hypertension, diabetes and cardiovascular disease.
“Understanding these differences is critical for safeguarding the vulnerable and guiding effective policy and treatments,” it states.
Using super resolution imaging, the Scripps team — led by Scott Hansen, an associate professor in Scripps’ Department of Molecular Medicine — documented a chain-reaction process that begins with high cholesterol levels and ends with a cytokine storm that fills the lungs with fluid.
Cells use cholesterol for many purposes, including mounting an immune response against SARS-CoV-2, the virus that causes COVID-19.
But COVID-19’s potentially lethal process begins with a high number of low-density lipoproteins or LDL — often referred to as bad cholesterol — circulating in the blood, accumulating in tissue and signaling cells of their presence.
The cells react by altering their membranes to make entry points and position receptors for cholesterol to enter.
But that process simultaneously makes available twice the number of locations for the virus optimally to dock with ACE2, which is the enzyme on the cell membrane that serves as an entry point for the virus to be drawn into the cell.
Excess cholesterol also helps the virus bind with ACE2, providing an easy access portal into the cell.
The problem is that the high virus count inside the cell spawns development of many cytokines — the proteins (peptides) that generate an inflammatory immune response against the SARS-CoV-2 virus inside and outside the cell.
Too many cytokines result in a “cytokine storm” — elevated inflammation levels that overwhelm the lungs and cause them to fill with fluid, which inhibit breathing and, if ventilation is unsuccessful, lead to death, the study found.
The role high cholesterol plays in that process, if confirmed, would clarify why obesity, hypertension, respiratory and cardiovascular diseases and diabetes represent such high risk factors for COVID-19 severity and mortality.
“As cholesterol increases with age and inflammation (e.g., smoking and diabetes), the cell surface is coated with viral entry points and optimally assembled viral entry proteins,” the study says.
It’s well-established that cholesterol levels generally increase with age — a point that runs parallel with the age-related severity and mortality rate from COVID-19.
“Understanding why young people are resistant in this class of [corona] viruses could help both healthy and chronically ill adults avoid severe symptoms of COVID19,” the study says. “Understanding these differences is critical for safeguarding the vulnerable and guiding effective policy and treatments.”
Based on cholesterol levels, age and inflammation levels, the study says, “we build a cholesterol-dependent model for COVID-19 lethality in elderly and the chronically ill.”
Study limits
In May, the Scripps study was posted on the bioRxiv website for research yet to be published in journals. It was done in a laboratory setting and did not involve the process as it actually would occur in animals or humans.
During the pandemic, the site has provided doctors and researchers with timely information about symptoms, drugs and health outcomes. Without it, physicians and researchers would wait months for such studies to be peer-reviewed and published in research journals.
But there’s also attendant risk of mistakes and false conclusions in such studies.
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.”
Blood vs. tissue
A correlation can exist between blood and tissue cholesterol levels.
“There is a link, but it’s not exactly one-to-one, and there are many other factors that increase tissue cholesterol, which is not dictated by blood cholesterol,” said Dr. Indu Poornima, an Allegheny Health Network cardiologist.
Such factors, among others, can include genetics, diet and drugs.
The Scripps study also noted people can reduce the risk of COVID-19 death by lowering cellular cholesterol. But Dr. Poornima said it’s important to note, however, that the experiments were done on cells and not on a whole animal or humans.
“The exact ways of lowering cellular cholesterol through medications is not clear,” she said.
The study notes that consuming polyunsaturated fatty acids found mostly in plant-based food sources “oppose the effects of cholesterol and provide a molecular basis for eating healthy diets to avoid severe cases of COVID-19.”
Dr. Poornima, who also directs the AHN Women’s Heart Center, said other studies have shown how cholesterol in liver tissue allows the hepatitis C virus to enter liver cells through a process similar to what’s described in the Scripps study.
For now, additional research is necessary to confirm or refute the Scripps study findings. Should it prove accurate, the study could lead to treatments to block the infection process and reduce future coronavirus deaths.
“If it turns out that statin drugs are protective, that would be a huge step moving forward,” Dr. Poornima said, suggesting one example.
The study also says that improvements in lifestyle can reduce the virus’ lifethreatening impacts by lowering cholesterol levels that accumulate in the tissue.
“Put saturated fat and cholesterol together — if that’s being eaten — then it provides a gateway for the virus to get into the cell,” said Mr. Hansen, who holds a Ph.D. in biochemistry and pharmacology. “People with a really poor diet with high cholesterol over a long period of time are sitting ducks for the virus.”
Giovanna Rappocciolo, an assistant professor in the University of Pittsburgh Graduate School of Public Health, Department of Infectious Diseases and Microbiology, has studied cholesterol’s impact on the human immunodeficiency virus and found the Scripps study to be plausible.
She said the Scripps study, however, is “rough around the edges” — a situation that could be remedied through the peer-review process.
But the study also is important, she said, in noting that COVID-19 potentially could be treated by manipulating cholesterol levels, with drugs already available.
For now, she said, “using available drugs directed to reduce cell cholesterol levels could represent an important line of inquiry.”
“Generally speaking, this is a very interesting and valid study that needs some more work,” said Ms. Rappocciolo, who holds a Ph.D. in immunology. “It opens up a new field of study to try to exploit these pathways to stop the infection of cells.”