Does cholesterol play a role in COVID-19?
A new study published in May 2020 suggests that the strikingly increased mortality in
COVID-19 patients who are either old or also have high blood pressure,
diabetes, cardiovascular disease is due to high tissue cholesterol
levels. It also indicates the role of a healthy diet, by showing that
polyunsaturated fatty acids (PUFA) in blood oppose the effects of
cholesterol and thus the risk for severe COVID-19 symptoms.
The current study aims to answer the question as to what controls the entry of SARS-CoV-2 into the host cell.
These GM-1 rafts migrate from areas of disordered lipids or polyunsaturated fats.
Cholesterol is a fat found in cell membranes all over the body and deposited in macrophage-rich tissues with chronic inflammation. In lung disease, lung cells, as well as macrophages, are observed to take cholesterol in and out. The study, therefore, focused on finding the relationship between the infective potential of the virus and the concentration of cholesterol.
In the cholesterol loading condition, the viral entry increased markedly by 50%, while it was significantly reduced in the unloading state. The addition of a cholesterol-removing chemical called methyl-beta-cyclodextrin (MβCD) to the cell culture duplicated the viral entry-inhibiting effect of cholesterol unloading. The researchers concluded that the lack of virus entry with the unloading of cholesterol is not due to a lack of ACE2 receptor, because the latter was expressed at normal high levels in the presence of both apoE and MβCD.
Having indicated the cholesterol-dependent entry of the virus, they examined the underlying molecular mechanisms. Cholesterol is essential to the number and size of GM1 rafts as well as the in and out movement of proteins into the rafts in the cell membrane. With an increase in these, the viral entry also goes up.
The researchers found that ACE2 receptors were correlated with GM1 lipid rafts more than 3-fold in the loaded condition of the cell. The opposite effect (an over 70% reduction in localization to the rafts) was seen with the addition of MβCD. Thus apoE-mediated cholesterol loading causes localization of ACE2 at the point of viral entry.
Variation in Infectivity Between Adults and Children
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19 disease, is known to infect and enter host cells employing the ACE2 receptor molecule present on the outside of the host cell membrane. It was initially thought that low ACE2 levels in children caused the decreased risk for this condition, but recent studies show that this is not necessarily always true. Some children show high ACE2 levels in early childhood.The current study aims to answer the question as to what controls the entry of SARS-CoV-2 into the host cell.
The Role of Cholesterol in Viral Entry
Earlier SARS-CoV viral research might help provide the answer. This virus enters the cell only in the presence of cholesterol and monosialotetrahexosylganglioside1 (GM1) in the form of lipid rafts, in culture. Cholesterol is required for the formation of these GM-1 lipid rafts, and viruses that attach here enter the cell by endocytosis.These GM-1 rafts migrate from areas of disordered lipids or polyunsaturated fats.
Cholesterol is a fat found in cell membranes all over the body and deposited in macrophage-rich tissues with chronic inflammation. In lung disease, lung cells, as well as macrophages, are observed to take cholesterol in and out. The study, therefore, focused on finding the relationship between the infective potential of the virus and the concentration of cholesterol.
Cholesterol Promotes Viral Entry
First, using a pseudovirus expressing the spike (S) protein of SARS-CoV-2, they loaded cholesterol into cultured cells along with the carrier protein apoE, and blood serum. The S protein is responsible for viral entry. In the cholesterol-bound form, the apoE protein binds to the LDL receptor of the cell to load cholesterol into the cell. If free, its binding promotes the unloading of cholesterol from the cell.In the cholesterol loading condition, the viral entry increased markedly by 50%, while it was significantly reduced in the unloading state. The addition of a cholesterol-removing chemical called methyl-beta-cyclodextrin (MβCD) to the cell culture duplicated the viral entry-inhibiting effect of cholesterol unloading. The researchers concluded that the lack of virus entry with the unloading of cholesterol is not due to a lack of ACE2 receptor, because the latter was expressed at normal high levels in the presence of both apoE and MβCD.
Having indicated the cholesterol-dependent entry of the virus, they examined the underlying molecular mechanisms. Cholesterol is essential to the number and size of GM1 rafts as well as the in and out movement of proteins into the rafts in the cell membrane. With an increase in these, the viral entry also goes up.
Cholesterol Facilitates Greater ACE2 Availability
The movement of ACE2 receptors to the viral entry site also increases with the cholesterol load. To find out how much of the receptor is localized in these raft sites, and how much this varies with the cholesterol concentration, they used fluorescent-labeled antibodies to ACE2 to cells treated with apoE and serum and used dSTORM (direct stochastical optical reconstruction microscopy) to acquire images of the lipid domain structure at the nanoscale.The researchers found that ACE2 receptors were correlated with GM1 lipid rafts more than 3-fold in the loaded condition of the cell. The opposite effect (an over 70% reduction in localization to the rafts) was seen with the addition of MβCD. Thus apoE-mediated cholesterol loading causes localization of ACE2 at the point of viral entry.
Why is COVID-19 So Much More Dangerous in the Old and Sick?
This cholesterol-dependent mechanism of ACE2 localization, as well as virus entry, could be why COVID-19 is so much more lethal in the elderly. Tissue cholesterol levels increase with age as a result of chronic disease conditions like atherosclerosis and other acute or chronic inflammations. These are the same conditions that are found to increase the severity and likelihood of symptomatic COVID-19 disease.
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