Since the outbreak of COVID-19 caused by SARS-CoV-2, approximately 1 million people have died and the total number of global confirmed cases was over 30 million as of 28 September 2020. Coronavirus tropism is predominantly determined by the interaction between coronavirus spike (S) proteins and their corresponding host receptors. The S protein of SARS-CoV-2 (SARS-2-S) can be cleaved into the S1 (SARS-2-S1) and S2 (SARS-2-S2) subunits, which are responsible for receptor recognition and membrane fusion. Binding of SARS-CoV-2 to ACE2 occurs via the C-terminal domain (also called the receptor-binding domain (RBD)) of SARS-2-S1. The observed incomplete inhibition mediated by ACE2 antibodies and the high neutralization potency of monoclonal antibodies (mAbs) targeting the N-terminal domain (NTD) of SARS-2-S1 suggest that SARS-CoV-2 might use other (co)receptors or other mechanisms for host cell entry.
SR-B1 is a cell-surface HDL receptor that mediates the selective uptake of cholesteryl esters and other lipid components of receptor-bound HDL particles. This cholesterol delivery system is well recognized in isolated hepatocytes, fibroblasts, adipocytes, macrophages, adrenal cells, ovarian cells and testicular Leydig cells. Interestingly, alveolar type II cells also express SR-B1, where it is responsible for vitamin E uptake, preferentially from HDL. SR-B1 has emerged as a critical receptor that affects HCV entry; however, a potential role of SR-B1 in SARS-CoV-2 infection is unknown.
Here we show that the high-density lipoprotein (HDL) scavenger receptor B type 1 (SR-B1) facilitates ACE2-dependent entry of SARS-CoV-2. We find 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. 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. We further show that SR-B1 is coexpressed with ACE2 in human pulmonary tissue and in several extrapulmonary tissues. Our findings reveal that SR-B1 acts as a host factor that promotes SARS-CoV-2 entry and may help explain viral tropism, 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.
With over 30 million people infected, COVID-19 represents a major public health problem of high socioeconomic impact. However, treatment options for COVID-19 are limited, and a vaccine for prevention against COVID-19 infection is currently not available. The results of our study demonstrate that SR-B1 facilitates SARS-CoV-2 cellular attachment, entry and infection. SARS-CoV-2 entry is inhibited by silencing SR-B1 expression and by SR-B1 antagonists. Moreover, SR-B1 expression levels have been shown to affect attachment, entry and replication of bona fide SARS-CoV-2 virus. Thus, as an entry cofactor, SR-B1 might represent a therapeutic target to limit SARS-CoV-2 infection.
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