Dengue virus infectivity depends on envelope protein binding to target cell heparan sulfate

Abstract

Dengue virus is a human pathogen that has reemerged as an increasingly important public health threat. We found that the cellular receptor utilized by dengue envelope protein to bind to target cells is a highly sulfated type of heparan sulfate. Heparin, highly sulfated heparan sulfate, and the polysulfonate pharmaceutical Suramin effectively prevented dengue virus infection of target cells, indicating that the envelope protein-target cell receptor interaction is a critical determinant of infectivity. The dengue envelope protein sequence includes two putative glycosaminoglycan-binding motifs at the carboxy terminus; the first could be structurally modeled and formed an unusual extended binding surface of basic amino acids. Similar motifs were also identified in the envelope proteins of other flaviviridae. Developing pharmaceuticals that inhibit target cell binding may be an effective strategy for treating flavivirus infections.

Isolation and characterization of heparan sulfate from various murine tissues

“…Our examination of porcine, bovine, and human liver HS [8,35] show that it is rich in highly sulfated sequences and that these are responsible for ApoE interaction [34]. Furthermore, these highly charged liver HS chains also appear to act as receptors for pathogens such as dengue virus [36] and malaria circumsporozoite [37]. It is interesting to note that mice, also sensitive to malaria, have a similar highly sulfated liver HS [38].…”

Basic chemokine-derived glycosaminoglycan binding peptides exert antiviral properties against dengue virus serotype 2, herpes simplex virus-1 and respiratory syncytial virus

“…DENV is one of the most important emerging viruses in tropical and subtropical countries with 2.5 billion people at risk to get infected and every year more than 50 million clinical cases of DENV infections [9]. Further, it was shown that several viruses such as HSV-1, hepatitis B virus (HBV), HIV-1, DENV, vaccinia virus (VV) and adenovirus (ADV) bind to glycosaminoglycans (GAGs) for entering and infecting the host cell [10][11][12][13][14][15][16][17][18][19]. GAGs are linear polysaccharides consisting of repeating disaccharide subunits which can be divided into six classes:…”

Dromedary glycosaminoglycans: Molecular characterization of camel lung and liver heparan sulfate

“…The amount of perlecan is very low in normal liver, but increases dramatically in liver fibrosis (Kovalszky et al, 1988). Liver is also a target for a number of pathogens and liver HS has been demonstrated in several cases to play a pivotal role in infectivity (Chen et al, 1997;Rathore et al, 2001;Barth et al, 2003). Liver HSPGs at the endothelial level act as critical receptors for apoE and is involved in lipid metabolism (Bocksch et al, 2001;Dong et al, 2001;Bazin et al, 2002).…”