Good cholesterol helps SARS-CoV-2 enter cells

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 19 (COVID-19) has infected over 63.18 million individuals worldwide and claimed over 1.46 million lives.

The virus 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.

Chinese researchers from Beijing Institute of Biotechnology, Academy of Military Medical Sciences (AMMS), China, led by Congwen Wei, the first author of the study, have found the role of an HDL (high-density lipoprotein) receptor in the facilitation of entry of the SARS CoV-2. Their study titled, “HDL-scavenger receptor B type 1 facilitates SARS-CoV-2 entry,” is published in the latest issue of the journal Nature Metabolism.

Study: HDL-scavenger receptor B type 1 facilitates SARS-CoV-2 entry. Image Credit: Kateryna Kon / Shutterstock
Study: HDL-scavenger receptor B type 1 facilitates SARS-CoV-2 entry. Image Credit: Kateryna Kon / Shutterstock

Background

The researchers 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).

Viral entry into the cell

They 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.

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:

  • 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
  • When monoclonal antibodies (mAbs) targeting the N-terminal domain (NTD) of SARS-2-S1 are used, there is a blockade in the viral entry into the host cell

HDL receptor

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. 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.

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.

Study design

The SARS-CoV-2 strain - BetaCoV/Beijing/IME-BJ01/2020, was used for this study. 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.

Findings

This study showed that HDL SR-B1 receptor facilitates ACE2-dependent entry of SARS-CoV-2. The overall results of the study were:

  • The S1 subunit of SARS-2-S binds to cholesterol and possibly to HDL components
  • This binding can enhance viral uptake as seen with in vitro experiments
  • 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.”
  • SR-B1 allows the entry of the SARS-CoV-2 in cells that express ACE2. This is done by increasing virus attachment.
  • 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.
  • Similarly, when pharmacological SR-B1 antagonists were used in the cultured cells, HDL enhanced infection with SARS CoV-2 was again inhibited
  • SR-B1 is expressed with ACE2 in human lung tissues and well as non-lung tissues
  • 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.”

Conclusions and implications

This study shows 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”. Overall this points to the fact that SR-B1 could be a potential therapeutic target to prevent the SARS-CoV-2 infection, the team writes in conclusion.

Journal reference:
Dr. Ananya Mandal

Written by

Dr. Ananya Mandal

Dr. Ananya Mandal is a doctor by profession, lecturer by vocation and a medical writer by passion. She specialized in Clinical Pharmacology after her bachelor's (MBBS). For her, health communication is not just writing complicated reviews for professionals but making medical knowledge understandable and available to the general public as well.

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