Coxsackievirus A24 Variant Uses Sialic Acid-Containing O -Linked Glycoconjugates as Cellular Receptors on Human Ocular Cells

Abstract

Coxsackievirus A24 variant (CVA24v) is a main causative agent of acute hemorrhagic conjunctivitis (AHC), which is a highly contagious eye infection. Previously it has been suggested that CVA24v uses sialic acidcontaining glycoconjugates as attachment receptors on corneal cells, but the nature of these receptors is poorly described. Here, we set out to characterize and identify the cellular components serving as receptors for CVA24v. Binding and infection experiments using corneal cells treated with deglycosylating enzymes or metabolic inhibitors of de novo glycosylation suggested that the receptor(s) used by CVA24v are constituted by sialylated O-linked glycans that are linked to one or more cell surface proteins but not to lipids. CVA24v bound better to mouse L929 cells overexpressing human P-selectin glycoprotein ligand-1 (PSGL-1) than to mocktransfected cells, suggesting that PSGL-1 is a candidate receptor for CVA24v. Finally, binding competition experiments using a library of mono-and oligosaccharides mimicking known PSGL-1 glycans suggested that CVA24v binds to Neu5Ac␣2,3Gal disaccharides (Neu5Ac is N-acetylneuraminic acid). These results provide further insights into the early steps of the CVA24v life cycle.

Turkey adenovirus 3, a siadenovirus, uses sialic acid on N-linked glycoproteins as a cellular receptor

“…It is noteworthy that SNA showed a relatively lower effect on reducing virus infection than MAL. Similar findings were reported for both bovine adenovirus 3 and human adenovirus 37, which infect kidney and conjunctival epithelial cells, respectively [18,49]. The absence of statistical significance of SNA effect could be attributed to high variability among the treatment groups.…”

Influenza A Virus-Induced Expression of a GalNAc Transferase, GALNT3, via MicroRNAs Is Required for Enhanced Viral Replication

“…In many studies, glycosylation has been shown to affect the viral attachment or penetration steps via the modification of cellular receptors or viral envelope glycoproteins. For instance, the O-linked glycoproteins of ␣2,3-or ␣2,6-linked sialic acids were shown to play important roles during infection by IAV and other viruses, including the coxsackievirus A24 variant and enterovirus 70 (42)(43)(44)(45). Furthermore, the envelope proteins of many viruses, such as human immunodeficiency virus type 1, HCV, Ebola virus, and herpes simplex virus 1, have been shown to be modified by O-linked glycosylation, which influences the attachment of viral virions to the cell surface (42,(46)(47)(48).…”

Sialoglycovirology of Lectins: Sialyl Glycan Binding of Enveloped and Non-enveloped Viruses

“…Several strains listed in Table 2 of small (+)ssRNA-containing viruses, pico-rna-viruses, in the family Picornaviridae, including equine rhinitis A virus (ERAV) in the genus Aphthovirus; [84][85][86]; EMCV has a wide host range including humans [87]; and low-neurovirulent TMEV is a mouse pathogen that is able to cause a chronic demyelinating disease and is thus used for studies on human multiple sclerosis [88] as shown in Table 2. The viral capsid of the picornaviruses comprises three virion proteins (VP1, VP2, and VP3) that form the shell and one virion protein (VP4) lying on the inner surface of the virus particle as illustrated in Fig.…”

“…Although both EV70 and CVA24v (but not CVA24) are still major causes of acute hemorrhagic conjunctivitis (AHC) epidemics worldwide due to ocular infections of both conjunctival and corneal cells and still have the potential to spark pandemics [96], there are no vaccines or antiviral drugs for AHC diseases caused by EV70 and CVA24v [86]. Knowledge of the receptor-binding specificity of viruses is needed for prevention and treatment of infections.…”

“…EV70 can bind to phosphatidylinositol-specific phospholipase C-treated cells and tunicamycin-treated cells but not to benzyl N-acetyl-α-D-galactosaminide (benzylGalNAc)-treated cells or to proteinase K-treated corneal cells, suggesting that EV70 prefers binding to α2-3Sia Oglycosylated, non-GPI-anchored glycoproteins on human corneal epithelial (HCE) cells [85,97]. Viral binding and infection studies using sialidase-, PNGase F-, tunicamycin-, or benzylGalNAc-treated/sialidase-, PNGase F-, tunicamycin-, or benzylGalNAcuntreated cells and binding competition assays in the presence of sialyl-Le x , 3 0 SLN, or 3 0 sialyl-TF (Neu5Acα2-3Galβ1-3GalNAcα1, TF, Thomsen-Friedenreich) suggested that CVA24v binds to and infects HCE cells via α2-3Neu5Ac O-linked cell surface proteins [86]. This shared α2-3Neu5Ac-binding preference could be a factor explaining why these viruses have overlapping cellular tropism.…”