One of the first elements evident during the early days of the COVID-19 pandemic was the virus’s strong effect on the elderly and those with pre-existing conditions, especially when compared with the little effect SARS-CoV-2 seemed to have on children.
Over time, scientists learned that SARS-CoV-2 uses the receptor angiotensin-converting enzyme 2, or ACE2, to infect human cells. However, ACE2 does not act alone in allowing the infiltrating virus. Rather, ACE2 is like a doorknob—only when SARS-CoV-2 grabs it and maneuvers it precisely can the virus open a doorway to infection. Even three years later, however, the identity of the door was unknown.
Until a research team at the University of Florida Scripps published their most recent work in the Journal of Biological Chemistry. As it turns out, the door is made up of cholesterol clusters, which at least partly explains SARS-CoV-2’s effect on older people. For example, from 2017 to 2020, 86.4 million U.S. adults age 20 or older had high or borderline high cholesterol in the blood.
During the study, associate professor Scott Hansen and team discovered that cholesterol-induced clustering—a condition common in chronic disease—causes ACE2 to move to endocytic ganglioside (GM1) lipids. GM1 lipids are a prime location for virus entry—and SARS-CoV-2 is no exception.
When the scientists compared ACE2 activity in cholesterol-loaded cells, it was about 40% more than ACE2 activity in human embryonic kidney cells after cholesterol depletion.
Hansen and colleagues also tested in mice, and found that age and a high-fat diet increase lung tissue cholesterol by up to 40%. In smokers with chronic disease, study results show cholesterol is elevated 2-fold.
“[That is] a magnitude of change that dramatically increases infectivity of the virus in cell culture,” Hansen said. “Increasing the ACE2 location near GM1 lipids increases viral infectivity and may help explain the selective severity of COVID-19 in aged and diseased populations.”
Fortunately, Hansen’s past research has shown that cholesterol-associated SARS-CoV-2 infection can be easily disrupted with exercise.
“Mechanical force and polyunsaturated fatty acids disrupt the aggregation of the cholesterol,” Hansen said. “Healthy mechanical force is achieved with exercise. In our studies, cells need to be jostled a little bit in order to keep the cholesterol from setting up in the cell membrane. Regular exercise with its increased heart rate and blood flow should reduce the cholesterol aggregates in the cell membranes.”
In addition to new insights on the entry mechanism of SARS-CoV-2, the study also highlighted the inaccuracies of the way doctors assess cholesterol risk. Currently, the only way to test cholesterol levels is via a blood test, but Hansen says that doesn’t account for the cholesterol that is in the process of leaving a patient’s body.
“Basically, cholesterol goes both ways,” the professor of molecular medicine said. “It gets loaded into cells, which is the forward pathway. But then there's reverse cholesterol transport where the body takes cholesterol back out of the cells and moves it to your liver and excretes it out of the body or recycles it. If you measure cholesterol levels in the blood, you don't know the levels in the tissue or if it is being taken out or brought in.”
Thus, the researchers are working with physicians to develop a more accurate test—one that focuses on the tissues and how cholesterol is taken up over time, rather than on blood, which changes depending on food intake.
“It’s a harder measurement, but, in the end, it may help people understand their risk for disease and save lives,” said Hansen.