Initial Step of Virus Entry: Virion Binding to Cell-Surface Glycans

Abstract

Virus infection is an intricate process that requires the concerted action of both viral and host cell components. Entry of viruses into cells is initiated by interactions between viral proteins and cell-surface receptors. Various cell-surface glycans function as initial, usually low-affinity attachment factors, providing a first anchor of the virus to the cell surface, and further facilitate high-affinity binding to virus-specific cell-surface receptors, while other glycans function as specific entry receptors themselves. It is now possible to rapidly identify specific glycan receptors using different techniques, define atomic-level structures of virus-glycan complexes, and study these interactions at the single-virion level. This review provides a detailed overview of the role of glycans in viral infection and highlights experimental approaches to study virus-glycan binding along with specific examples. In particular, we highlight the development of the atomic force microscope to investigate interactions with glycans at the single-virion level directly on living mammalian cells, which offers new perspectives to better understand virus-glycan interactions in physiologically relevant conditions. Expected final online publication date for the Annual Review of Virology, Volume 7 is September 29, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2

“…Given its location, viruses and other infectious organisms must pass through the glycocalyx to engage receptors thought to mediate viral entry into host cells. Many viral pathogens have evolved to utilize glycans as attachment factors, which facilitates the initial interaction with host cells, including influenza virus, herpes simplex virus, human immunodeficiency virus, and different coronaviruses (SARS-CoV-1 and MERS-CoV) (Cagno et al, 2019;Koehler et al, 2020;Stencel-Baerenwald et al, 2014). Several viruses interact with sialic acids, which are located on the ends of glycans found in glycolipids and glycoproteins.…”

SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2

“…Given its location, viruses and other infectious organisms, must pass through the glycocalyx to engage receptors thought to mediate viral entry into host cells. Many viral pathogens utilize glycans as attachment factors to facilitate the initial interaction with host cells, including influenza virus, Herpes simplex virus, human immunodeficiency virus, and different coronaviruses (SARS-CoV-1 and MERS) (Cagno et al, 2019;Koehler et al, 2020;Stencel-Baerenwald et al, 2014). Several viruses interact with sialic acids, which are located on the ends of glycans found in glycolipids and glycoproteins (Varki et al, 2015).…”

A Tethered Ligand Assay to Probe the SARS-CoV-2 ACE2 Interaction under Constant Force

“…Our measured lifetime of the initial RBD ACE2 interaction is much longer than the values < 1 s reported for influenza, rabies, or HIV viruses engaging their cellular receptors measured by AFM or optical tweezers force spectroscopy 12,13,50,51 , which might contribute to SARS-CoV-2 higher infectivity. For influenza, rabies, and HIV multivalent interactions of the virus with its host cell have been suggested to play important roles 12,13,14 . Our data suggest that if held in close proximity, SARS-CoV RBDs can engage ACE2 rapidly, within τ 0,open ~ 1 ms.…”

“…The homotrimeric nature of S, combined with the dense coverage of the viral capsid surface by S trimers 1 and the observation that ACE2 clusters on the apical site of cells 3 imply a high local density of binding partners. Consequently, an initial binding event could rapidly lead to further engagement of additional ligand-receptor pairs 11 as has been suggested for a number of other viruses, including influenza, rabies, and HIV 12,13,14 . Stable binding of S to ACE2 enables further downstream events such as cleavage of S by furine or TMPRSS2 proteases 5,11,15 , triggering conformational changes, and ultimately fusion with the cell membrane and cellular entry.…”