Heparan Sulfate Proteoglycans Initiate Dengue Virus Infection of Hepatocytes

Abstract

The clinical pictures caused by the arthropod-borne dengue viruses (DEN), which belong to the family of Flaviviridae, vary from a simple febrile fatigue to severe hemorrhagic fever and the often rapidly fatal dengue shock syndrome. 1 Consistent with a worldwide escalation of infection rates during the last decade, the more severe manifestations are occurring in an increasing proportion of cases. 2 Although DEN infections are a particular threat in tropical and subtropical regions, endemic transmission has recently returned to the continental United States. 3 The role of the liver in DEN infection has been generally underestimated, although the infection is regularly associated with elevated liver enzymes. More recent reports suggest the liver to be one of the ultimate target organs and hepatocytes a major site of viral replication in vivo. 4,5 In a frequent number of cases DEN infection causes acute hepatitis with liver failure and hepatic encephalopathy. 6-9 Aside from their own impact on liver cells, DEN provides a potential model for hepatitis C virus (HCV) infection, which at present cannot be grown in cell culture or small animal models.Although the initial steps of infection are a critical determinant of tissue tropism and therefore pathogenesis, little is known about the molecular basis of DEN-or of any other flavivirus-binding to their target cells, and the endocytic itineraries they follow. A growing list of structurally different viruses and certain other microbial agents have been previously shown to utilize sulfated glycosaminoglycans (GAG) such as heparan sulfates (HS) for initial binding to target cells. [10][11][12][13][14][15][16][17] HS is a repeating highly negative-charged linear copolymer of variably sulfated uronic acid and glucosamine carbohydrate residues. 18 Cell surface HS are attached to protein core molecules, some of which are transmembrane proteins with conserved cytoplasmic domains, capable of intracellular signaling. 19 These heparan sulfate proteoglycans (HSPG) provide the main GAG proportion of the cell surface. The presumed physiologic function of these molecules is the promotion of cellular adhesion to the extracellular matrix and the maintenance of boundaries between tissues of different types. 20 They are known to bind a large number of polypeptide growth factors and are involved in intracellular signaling in response to these molecules. 21 HSPG are ubiquitously distributed in the matrix and cell membrane of most tissues, but a distinct cell-and tissue-specific expression pattern 22 may contribute to differential targeting of viruses. They are not believed to be the sole mediator of viral uptake, although endosomal cycling of some HSPG subtypes have been described. 23 This led to the suggestion that infection of different viruses might be a two-or multi-step process, initial contact being with a low-affinity HSPG-receptor followed by transfer to the high-affinity receptor for internalization. 10,24,25 Internalization of flaviviruses is generally believed to be a receptor-med...

Resistance to Dengue Virus Infection in Mice Is Potentiated by CXCL10 and Is Independent of CXCL10-Mediated Leukocyte Recruitment

“…Because CXCL10 is the predominant CXCR3 ligand induced by DENV infection (17,26,28) but was not critical for recruitment of effector cells, we examined other potential antiviral mechanisms. Previously, we demonstrated that CXCL10 inhibits DENV entry into hepatocytes by competing with DENV for binding to the cell surface heparan sulfate (31), a coreceptor for DENV entry (44)(45)(46). In the current study, we demonstrated that CXCL10 also competes with DENV for binding to heparan sulfate on the surface of neurons, thus preventing DENV entry and reducing infectivity.…”

Adeno-Associated Viral Vectors Based on Serotype 3b Use Components of the Fibroblast Growth Factor Receptor Signaling Complex for Efficient Transduction

“…Infectivity of certain viruses including AAV2 is inhibited in the presence of soluble heparin (Summerford and Samulski, 1998;Dechecchi et al, 2000;Hilgard and Stockert, 2000). Presumably, heparin attaches to heparinbinding sites on the viral particle, directly blocking infection.…”

Dengue Virus Cellular Receptors and Tropism

“…Glycosaminoglycans (GAGs) and other attachment factors The first molecule that was identified to participate in DENV entry into mammalian cells was heparan sulfate [20][21][22]. Highly sulfated GAGs are ubiquitous molecules present on the surface of several types of cells, also mediating attachment for many viruses [23].…”