Glycosylation is a key in SARS-CoV-2 infection

Abstract

SARS-CoV-2 causes the respiratory syndrome COVID-19 and is responsible for the current pandemic. The S protein of SARS-CoV-2-mediating virus binding to target cells and subsequent viral uptake is extensively glycosylated. Here we focus on how glycosylation of both SARS-CoV-2 and target cells crucially impacts SARS-CoV-2 infection at different levels: (1) virus binding and entry to host cells, with glycosaminoglycans of host cells acting as a necessary co-factor for SARS-CoV-2 infection by interacting with the receptor-binding domain of the SARS-CoV-2 spike glycoprotein, (2) innate and adaptive immune response where glycosylation plays both a protective role and contributes to immune evasion by masking of viral polypeptide epitopes and may add to the cytokine cascade via non-fucosylated IgG, and (3) therapy and vaccination where a monoclonal antibody-neutralizing SARS-CoV-2 was shown to interact also with a distinct glycan epitope on the SARS-CoV-2 spike protein. These evidences highlight the importance of ensuring that glycans are considered when tackling this disease, particularly in the development of vaccines, therapeutic strategies and serological testing.

Keywords: Blood group antigen; COVID-19; Glycosylation; Infection; SARS-CoV-2; Spike protein.

Fig. 1

Spike (S) glycoprotein gene-based phylogenetic analysis. The analysis includes all five defined subgenera of Betacoronaviruses, namely, Sarbecovirus, Embecovirus, Merbecovirus, Nobecovirus and Hibecovirus. The isolates in the gray area are from the current outbreak of SARS-CoV-2 from around the world. The nearest neighbors of SARS-CoV-2 are the bat-SL-CoV, encircled in yellow (from [3] with permission)

Fig. 2

Role of glycosylation in SARS-CoV-2 biology and COVID-19 pathogenesis

Fig. 3

Steps of replication and subcellular site glycosylation of pathogenetic human coronaviruses (adapted from [10] with permission)

Fig. 4

Proposed mechanisms of glycan-mediated host invasion of SARS-CoV-2. Receptor binding and invasion are facilitated by the interaction of its S protein with (1) heparan sulfate, ACE-2 receptors via (2a) glycan-glycan, (2b) glycan-protein, (2c) protein-protein interactions, (3) sialic acids and (4) lectins. In addition, A/B blood antigens (5) at the virion surface may prevent infection in a potential host producing blood group-specific antibodies. ✓ indicates inter-molecular interactions that promote receptor binding and invasion. X indicates glycan-mediated interactions that may prevent infection

Fig. 5

Human blood group antigens. Yellow circle, galactose; yellow square, N-acetyl galactosamine; red triangle, fucose