How SARS-CoV-2 spike binds to multiple host receptors

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein is partially responsible for the virus' pathogenicity. It is well known that the receptor-binding domain (RBD) of the S1 subunit of the S protein can bind to the angiotensin-converting enzyme 2 (ACE2) receptors, thus allowing viral entry into the host cell. Comparatively, the N terminal domain of the S2 subunit is responsible for membrane fusion.

Study: SARS-CoV-2 S glycoprotein binding to multiple host receptors enables cell entry and infection. Image Credit: Dotted Yeti /

Recent reports have shown that the S glycoprotein is capable of interacting with multiple alternate cell receptors. Researchers from the Genos Glycoscience Research Laboratory in Croatia have recently investigated the sites that the S protein is capable of binding with.

Additional receptors for SARS-CoV-2

Each protomer of the S glycoprotein contains 22 N-glycosylation sites and three O-glycosylation sites. Previous studies show inconsistent results when characterizing glycosylation, with some researchers showing full N-glycosylation the majority of the time, and others only partial glycosylation.

There has also been disagreement about the type of glycans found, with alternate studies showing hybrids, high-mannose, and complex N-glycans. This variation may be due to the method by which the S glycoprotein is glycosylated, as it uses the hosts’ glycosylation mechanisms that ultimately result in patterns similar to the host cells. This would result in different glycosylation patterns and different types of glycans, depending on the type of cell that the particular virus was constructed in.

The binding of the SARS-CoV-2 RBD to ACE2 is facilitated by the glycosaminoglycan heparan sulfate interaction of cellular glycocalyx, which aids the S protein structure to a more open conformation. However, while ACE2 is the primary receptor for SARS-CoV-2 cell entry, it shows low expression in the respiratory system.

Given that SARS-CoV-2 primarily spreads between hosts through droplet infection, this indicates that the S glycoprotein can interact with other receptors in order to enter the cell. Nuclear Magnetic Resonance (NMR) spectroscopy has recently shown that N glycans of the RBD can bind to various lectins, including macrophage galactose lectin (MGL), galectins -3, -7, and -8, as well as sialic acid-binding immunoglobulin-type lectin.

Expression levels of MGL have been found to be elevated in patients with severe coronavirus disease 2019 (COVID-19). This observation potentially suggests that the virus could respond to immune reactions through cell entry via these receptors.

Potentially more worrying is the possibility of the S glycoprotein binding to C-type lectin receptors (CLRs). These can be bound by oligomannose N-glycans; in fact, approximately 1 out of every 3 SARS-CoV-2 S glycans are of this type.

CLRs are primarily found on antigen-presenting cells, such as macrophages and dendritic cells. Both of these cell types are often found in the lungs. In fact, when inflammation occurs, monocytes circling in the blood and other tissues can also differentiate into these cells. This would provide both an initial route for infection in the respiratory system if ACE2 showed low expression, and for viral entry into cells in the bloodstream.

Macrophage galactose lectin (MGL) is another receptor primarily expressed in dendritic cells and macrophages in the human lungs and respiratory system. MGL recognizes glycans bearing terminal galactose.

It has been demonstrated that SARS-CoV-2 is able to bind to this lectin, further supporting the belief that the virus has alternate routes for cell entry. Further examination into the amino acid sequencing suggests that both N and O glycans are involved in MGL binding.


Taken together, the authors find the reviewed studies show that the SARS-CoV-2 S glycoprotein can bind to multiple other receptors, both allowing trans-infection of susceptible cells, as well as allowing more types of cells to be infected. The trans-infection of cells will not only lead to greater viral transmission but as the types of cells vulnerable to trans-infection are mostly immune cells, this could exacerbate the risk of severe inflammation and cytokine release.

Furthermore, the glycosylation-mediated interactions with SARS-CoV-2 could suggest that the glycosylation of SARS-CoV-2 could have significant effects on the severity of the disease in the patient, to the extent where it could determine recovery or spread. This suggests a mechanism for asymptotic SARS-CoV-2 infection, as a decreased titer of SARS-CoV-2 due to endocytosis by immune cells in the lungs may prevent symptoms from appearing.

Journal reference:
Sam Hancock

Written by

Sam Hancock

Sam completed his MSci in Genetics at the University of Nottingham in 2019, fuelled initially by an interest in genetic ageing. As part of his degree, he also investigated the role of rnh genes in originless replication in archaea.


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