Sulfated Glycosaminoglycans as Viral Decoy Receptors for Human Adenovirus Type 37

Abstract

Glycans on plasma membranes and in secretions play important roles in infection by many viruses. Species D human adenovirus type 37 (HAdV-D37) is a major cause of epidemic keratoconjunctivitis (EKC) and infects target cells by interacting with sialic acid (SA)-containing glycans via the fiber knob domain of the viral fiber protein. HAdV-D37 also interacts with sulfated glycosaminoglycans (GAGs), but the outcome of this interaction remains unknown. Here, we investigated the molecular requirements of HAdV-D37 fiber knob:GAG interactions using a GAG microarray and demonstrated that fiber knob interacts with a broad range of sulfated GAGs. These interactions were corroborated in cell-based assays and by surface plasmon resonance analysis. Removal of heparan sulfate (HS) and sulfate groups from human corneal epithelial (HCE) cells by heparinase III and sodium chlorate treatments, respectively, reduced HAdV-D37 binding to cells. Remarkably, removal of HS by heparinase III enhanced the virus infection. Our results suggest that interaction of HAdV-D37 with sulfated GAGs in secretions and on plasma membranes prevents/delays the virus binding to SA-containing receptors and inhibits subsequent infection. We also found abundant HS in the basement membrane of the human corneal epithelium, which may act as a barrier to sub-epithelial infection. Collectively, our findings provide novel insights into the role of GAGs as viral decoy receptors and highlight the therapeutic potential of GAGs and/or GAG-mimetics in HAdV-D37 infection.

Coronaviruses: Is Sialic Acid a Gate to the Eye of Cytokine Storm? From the Entry to the Effects

“…For example, the receptor-binding specificity of human influenza viruses is focused preferably on α2-3- and α2-6-linked sialic acids which predominates on epithelial cells in the nasal mucosa, pharynx, larynx, trachea and ocular cells and strongly correlate with clinical symptoms [ 36 , 37 , 38 , 39 ]. The binding of α2-3- and/or α2-6-linked sialic acids as cellular receptors recruited in the host cell entry processes was described in several viral families isolated from humans, including Adenoviridae , Picornaviridae , Reoviridae , Paramyxoviridae and Polyomaviridae [ 40 , 41 , 42 , 43 , 44 ]. In the context of the virus-host interaction, some viruses genera employ the sialic acid- and Siglec-based mechanisms that avoid or deactivates host defence after pathogen invasion and underlie in the pathogenesis of acquired immune deficiency syndrome (AIDS) [ 45 , 46 , 47 , 48 ].…”

Genomic foundations of evolution and ocular pathogenesis in human adenovirus species D

“…Therefore, although the presence of virions in the corneal stroma, even from disparate HAdV‐D types, will variably induce inflammation, tropism of specific HAdV‐Ds for the cornea is clearly not determined by the hexon protein. The fiber knob is the specific ligand on the adenovirus that first engages the host target cell, and its binding is currently a prime target for experimental therapies against EKC . Previous data showed a single amino acid substitution in HAdV‐D19 fiber knob, from glutamine to lysine at amino acid 240 (numbered according to HAdV‐D37), conferred binding to the immortalized Chang C human conjunctival cell line (now known to be HeLa cell contaminated) .…”

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

“…On the other hand, adenovirus fibre protein knob domains can bind to a wide variety of cell-surface molecules as attachment receptors. These molecules include coxsackievirus-adenovirus receptor (CAR), major histocompatibility class I, vascular cell adhesion molecule-1 (VCAM-1), heparan sulfate proteoglycan/glycosaminoglycans (HSPG/HS-GAGs), sialic acids, CD46 (a membrane cofactor protein), CD80(B7-1)/CD86(B7-2), desmoglein 2 and ganglioside disialylated glycan (GD1a) [17][18][19][20][21][22][23][24][25][26][27]. Terminal sialic acids on the cell surface are attached to the underlying polysaccharide chains via two major types of glycosidic bonds: α−2,3 and α−2,6.…”