COVID-19 Research: Study Shows That High-Density Lipoproteins (HDL) Or ‘Good’ Cholesterol Facilitates SARS-CoV-2 Cell Entry

COVID-19 Research: Chinese researchers from the Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS)-China led by Professor Dr Wei Congwen, have found the role of an HDL (high-density lipoprotein) receptor in the facilitation of entry of the SARS CoV-2 into human host cells.


 
The SARS-CoV-2 infects host cells through binding of the viral spike protein (SARS-2-S) to the cell-surface receptor angiotensin-converting enzyme 2 (ACE2).
 
In this research, the study team shows that the high-density lipoprotein (HDL) scavenger receptor B type 1 (SR-B1) facilitates ACE2-dependent entry of SARS-CoV-2.
 
The study team found that the S1 subunit of SARS-2-S binds to cholesterol and possibly to HDL components to enhance viral uptake in vitro. SR-B1 expression facilitates SARS-CoV-2 entry into ACE2-expressing cells by augmenting virus attachment.
 
Importantly blockade of the cholesterol-binding site on SARS-2-S1 with a monoclonal antibody, or treatment of cultured cells with pharmacological SR-B1 antagonists, inhibits HDL-enhanced SARS-CoV-2 infection.
 
The team further showed that SR-B1 is co-expressed with ACE2 in human pulmonary tissue and in several extrapulmonary tissues.
 
The study findings reveal that SR-B1 acts as a host factor that promotes SARS-CoV-2 entry and may help explain viral tropism and also identify a possible molecular connection between COVID-19 and lipoprotein metabolism, and highlight SR-B1 as a potential therapeutic target to interfere with SARS-CoV-2 infection.
 
The study findings were published in the peer-reviewed journal: Nature Metabolism. https://www.nature.com/articles/s42255-020-00324-0
 
The SARS-CoV-2 coronavirus that causes the COVID-19 disease has infected over 63.3 million individuals worldwide and claimed over 1.47 million lives.
 
The SARS-CoV-2 coronavirus that was first detected late last year is still a relatively new entity for researchers. New facts about SARS-CoV-2’s mode of infection, and transmission are still being discovered as the pandemic rages on.
 
The study  explained that the SARS-CoV-2 can infect human host cells after its viral spike protein (SARS-2-S) binds to a cellular surface receptor called the angiotensin-converting enzyme 2 (ACE2).
 
The team added that this binding of the coronavirus spike (S) proteins and their corresponding host receptors is key to the infection. When the two bind, the S protein of SARS-CoV-2 is broken or cleaved into two parts - S1 (SARS-2-S1) and S2 (SARS-2-S2) subunits. These subunits are key players that allow for receptor recognition and ultimately, fusion of the viral and cellular membranes so that the virus can enter the host cell.
 
Notably the SARS-CoV-2 and ACE2 bind using the C-terminal domain (also called the receptor-binding domain (RBD)) of SARS-2-S1. While this is known, two things come into question:
 
Firstly -ACE2 antibodies cannot block the viral entry into the host cell, suggesting it may not be the only way the virus enters the host cell
 
Secondly -When monoclonal antibodies (mAbs) ta rgeting the N-terminal domain (NTD) of SARS-2-S1 are used, there is a blockade in the viral entry into the host cell
 
The scavenger Receptor B1 (SR-B1) is a cell-surface HDL receptor. It is known to allow uptake of the cholesteryl esters and other lipid components of receptor-bound HDL particles in a normal system.
 
Interestingly this process is seen in several organs of the body, including the liver, fat cells, fibroblast cells, macrophages, ovary, and testicular Leydig cells, cells of the adrenal gland, etc. Cells of the lungs, called the alveolar type II cells, also possess SR-B1. Here they allow uptake of vitamin E from HDL.
 
Past studies have shown that the SR-B1 receptor allows entry of the hepatitis C virus, and its role in the entry of the SARS CoV-2 is being studied.
 
In this study, the SARS-CoV-2 strain - BetaCoV/Beijing/IME-BJ01/2020, was used.
 
All the cells were tested for expression of surface SR-B1 or ACE2 using flow cytometry. To check for SARS-2-S cell-surface binding, SARS-2-S proteins (140 nM) and HDL (6 μg ml−1) were tested. Immunohistochemical staining for ACE2 and SR-B1 was then done.
 
The study findings showed that HDL SR-B1 receptor facilitates ACE2-dependent entry of SARS-CoV-2.
 
The key findings of the study were:
 
-1. The S1 subunit of SARS-2-S binds to cholesterol and possibly to HDL components
 
-2. This binding can enhance viral uptake as seen with in vitro experiments
 
-3. The team writes, “Microscale thermophoresis (MST) assay showed that SARS-2-S could bind to cholesterol but did not bind campesterol or epicholesterol...”. They explained, “SARS-2-RBD bound to cholesterol and HDL, or its components, in the MST assay.”
 
-4. SR-B1 allows the entry of the SARS-CoV-2 in cells that express ACE2. This is done by increasing virus attachment.
 
-5. When the cholesterol-binding site on SARS-2-S1 was blocked using a monoclonal antibody, the HDL enhanced infection with SARS CoV-2 was inhibited.
 
-6. Similarly, when pharmacological SR-B1 antagonists were used in the cultured cells, HDL enhanced infection with SARS CoV-2 was again inhibited
 
-7. SR-B1 is expressed with ACE2 in human lung tissues and well as non-lung tissues
 
-8. The authors of the study write, “SARS-CoV-2 has been reported to attack multiple-organ systems and distribution analysis of SR-B1 in susceptible cells at the site of infection could shed new light on the tropism and potential transmission routes of the virus.”
 
Importantly the study findings show that SR-B1 acts as a host factor and also promotes the entry of the SARS-CoV-2 into the host cells. The researchers say that their findings show that there could be a “possible molecular connection between COVID-19 and lipoprotein metabolism”.
 
The study team concludes that overall this points to the fact that SR-B1 could be a potential therapeutic target to prevent the SARS-CoV-2 infection.

They added, ”Identifying SR-B1 as a SARS-CoV-2 entry cofactor, we propose that drugs that target SR-B1 could act as antivirals that limit SARS-CoV-2 infection. As a proof of concept, we have shown that ITX 5601, a clinically approved inhibitor of HCV infection, strongly inhibits SARS-CoV-2 infection of cultured cells. We propose that further testing of ITX 5601 in animal models of SARS-CoV-2 infection is warranted. “

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