Heparan Sulfate Proteoglycans Are Required for Cellular Binding of the Hepatitis E Virus ORF2 Capsid Protein and for Viral Infection
15 Dec 2009-Journal of Virology (American Society for Microbiology)-Vol. 83, Iss: 24, pp 12714-12724
TL;DR: It is demonstrated that cell surface heparan sulfate proteoglycans (HSPGs), specifically syndecans, play a crucial role in the binding of pORF2 to Huh-7 liver cells, indicating that a nonenveloped virus like HEV may have also evolved to use HSPGs as cellular attachment receptors.
Abstract: The hepatitis E virus (HEV), a nonenveloped RNA virus, is the causative agent of hepatitis E. The mode by which HEV attaches to and enters into target cells for productive infection remains unidentified. Open reading frame 2 (ORF2) of HEV encodes its major capsid protein, pORF2, which is likely to have the determinants for virus attachment and entry. Using an ∼56-kDa recombinant pORF2 that can self-assemble as virus-like particles, we demonstrated that cell surface heparan sulfate proteoglycans (HSPGs), specifically syndecans, play a crucial role in the binding of pORF2 to Huh-7 liver cells. Removal of cell surface heparan sulfate by enzymatic (heparinase) or chemical (sodium chlorate) treatment of cells or competition with heparin, heparan sulfate, and their oversulfated derivatives caused a marked reduction in pORF2 binding to the cells. Syndecan-1 is the most abundant proteoglycan present on these cells and, hence, plays a key role in pORF2 binding. Specificity is likely to be dictated by well-defined sulfation patterns on syndecans. We show that pORF2 binds syndecans predominantly via 6-O sulfation, indicating that binding is not entirely due to random electrostatic interactions. Using an in vitro infection system, we also showed a marked reduction in HEV infection of heparinase-treated cells. Our results indicate that, analogous to some enveloped viruses, a nonenveloped virus like HEV may have also evolved to use HSPGs as cellular attachment receptors.
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TL;DR: In this comprehensive review, the current knowledge about the virus itself, as well as the epidemiology, diagnostics, natural history, and management of HEV infection in developing and developed countries are summarized.
Abstract: Hepatitis E virus (HEV) infection is a worldwide disease. An improved understanding of the natural history of HEV infection has been achieved within the last decade. Several reservoirs and transmission modes have been identified. Hepatitis E is an underdiagnosed disease, in part due to the use of serological assays with low sensitivity. However, diagnostic tools, including nucleic acid-based tests, have been improved. The epidemiology and clinical features of hepatitis E differ between developing and developed countries. HEV infection is usually an acute self-limiting disease, but in developed countries it causes chronic infection with rapidly progressive cirrhosis in organ transplant recipients, patients with hematological malignancy requiring chemotherapy, and individuals with HIV. HEV also causes extrahepatic manifestations, including a number of neurological syndromes and renal injury. Acute infection usually requires no treatment, but chronic infection should be treated by reducing immunosuppression in transplant patients and/or the use of antiviral therapy. In this comprehensive review, we summarize the current knowledge about the virus itself, as well as the epidemiology, diagnostics, natural history, and management of HEV infection in developing and developed countries.
499 citations
Cites background from "Heparan Sulfate Proteoglycans Are R..."
...ORF2 encodes the viral capsid protein of 660 amino acids that is responsible for virion assembly (76), interaction with target cells (77, 78), and immunogenicity (79)....
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16 Nov 2017
TL;DR: HEV infections can be diagnosed by measuring anti-HEV antibodies, HEV RNA or viral capsid antigen in blood or stool and management of immunocompromised individuals involves lowering the dose of immunosuppressive drugs and/or treatment with the antiviral agent ribavirin.
Abstract: Hepatitis E virus (HEV) infection can lead to acute and chronic hepatitis as well as to extrahepatic manifestations such as neurological and renal disease; it is the most common cause of acute viral hepatitis worldwide. Four genotypes are responsible for most infection in humans, of which HEV genotypes 1 and 2 are obligate human pathogens and HEV genotypes 3 and 4 are mostly zoonotic. Until quite recently, HEV was considered to be mainly responsible for epidemics of acute hepatitis in developing regions owing to contamination of drinking water supplies with human faeces. However, HEV is increasingly being recognized as endemic in some developed regions. In this setting, infections occur through zoonotic transmission or contaminated blood products and can cause chronic hepatitis in immunocompromised individuals. HEV infections can be diagnosed by measuring anti-HEV antibodies, HEV RNA or viral capsid antigen in blood or stool. Although an effective HEV vaccine exists, it is only licensed for use in China. Acute hepatitis E is usually self-limiting and does not require specific treatment. Management of immunocompromised individuals involves lowering the dose of immunosuppressive drugs and/or treatment with the antiviral agent ribavirin.
325 citations
Cites background from "Heparan Sulfate Proteoglycans Are R..."
...ORF2 encodes the viral capsid protein of 660 amino acids that is responsible for virion assembly (76), interaction with target cells (77, 78), and immunogenicity (79)....
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TL;DR: The key molecular functions of syndecan-1 in modulating the onset, progression, and resolution of inflammatory diseases, cancer, and infection are discussed.
288 citations
TL;DR: Recent research into the shedding of syndecan cell‐surface proteoglycans and its physiological relevance are assessed.
Abstract: Proteolytic processes in the extracellular matrix are a major influence on cell adhesion, migration, survival, differentiation and proliferation. The syndecan cell-surface proteoglycans are important mediators of cell spreading on extracellular matrix and respond to growth factors and other biologically active polypeptides. The ectodomain of each syndecan is constitutively shed from many cultured cells, but is accelerated in response to wound healing and diverse pathophysiological events. Ectodomain shedding is an important regulatory mechanism, because it rapidly changes surface receptor dynamics and generates soluble ectodomains that can function as paracrine or autocrine effectors, or competitive inhibitors. It is known that the family of syndecans can be shed by a variety of matrix proteinase, including many metzincins. Shedding is particularly active in proliferating and invasive cells, such as cancer cells, where cell-surface components are continually released. Here, recent research into the shedding of syndecans and its physiological relevance are assessed.
287 citations
TL;DR: This review summarizes the current knowledge on the pathogenesis and treatment of HEV infection and explains why it has a more severe course in pregnant women.
281 citations
References
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TL;DR: Current analyses of genetic defects in Drosophila melanogaster, mice, and humans confirm most of these activities in vivo and identify additional processes that involve cell surface heparan sulfate proteoglycans.
Abstract: The heparan sulfate on the surface of all adherent cells modulates the actions of a large number of extracellular ligands. Members of both cell surface heparan sulfate proteoglycan families, the transmembrane syndecans and the glycosylphosphoinositide-linked glypicans, bind these ligands and enhance formation of their receptor-signaling complexes. These heparan sulfate proteoglycans also immobilize and regulate the turnover of ligands that act at the cell surface. The extracellular domains of these proteoglycans can be shed from the cell surface, generating soluble heparan sulfate proteoglycans that can inhibit interactions at the cell surface. Recent analyses of genetic defects in Drosophila melanogaster, mice, and humans confirm most of these activities in vivo and identify additional processes that involve cell surface heparan sulfate proteoglycans. This chapter focuses on the mechanisms underlying these activities and on the cellular functions that they regulate.
2,680 citations
"Heparan Sulfate Proteoglycans Are R..." refers background in this paper
...The HSPGs also interact with numerous biological effector molecules, such as growth factors and their receptors, extracellular matrix proteins, and cell-cell adhesion molecules, and are known to provide docking sites for the binding of various enveloped viruses and other microorganisms to eukaryotic cells (5)....
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...The chains are generally 50 to 150 disaccharide units in length and can be sulfated at several positions on the disaccharide units (5, 35)....
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TL;DR: An enzyme, "chondroitinase-ABC," has been purified to apparent homogeneity from extracts of Proteus vulgaris, NCTC 4636, which was adapted on a medium containing chondroit in sulfate C, and its properties have been compared with those of chondro-4-sulfatase- ABC from P. vulgaris.
1,206 citations
"Heparan Sulfate Proteoglycans Are R..." refers background in this paper
...To test whether pORF2 binding was mediated by chondroitin sulfate, Huh-7 cells were treated with chondroitin ABC lyase, which specifically cleaves glycosidic linkages in chondroitin sulfates A, B, and C (68)....
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TL;DR: The discovery of swine HEV not only has implications for HEV vaccine development, diagnosis, and biology, but also raises a potential public health concern for zoonosis or xenozoonosis following xenotransplantation with pig organs.
Abstract: A novel virus, designated swine hepatitis E virus (swine HEV), was identified in pigs. Swine HEV crossreacts with antibody to the human HEV capsid antigen. Swine HEV is a ubiquitous agent and the majority of swine ≥3 months of age in herds from the midwestern United States were seropositive. Young pigs naturally infected by swine HEV were clinically normal but had microscopic evidence of hepatitis, and developed viremia prior to seroconversion. The entire ORFs 2 and 3 were amplified by reverse transcription–PCR from sera of naturally infected pigs. The putative capsid gene (ORF2) of swine HEV shared about 79–80% sequence identity at the nucleotide level and 90–92% identity at the amino acid level with human HEV strains. The small ORF3 of swine HEV had 83–85% nucleotide sequence identity and 77–82% amino acid identity with human HEV strains. Phylogenetic analyses showed that swine HEV is closely related to, but distinct from, human HEV strains. The discovery of swine HEV not only has implications for HEV vaccine development, diagnosis, and biology, but also raises a potential public health concern for zoonosis or xenozoonosis following xenotransplantation with pig organs.
1,088 citations
TL;DR: It is shown that heparan sulfate modified by a subset of the multiple D-glucosaminyl 3-O-sulfotransferase isoforms provides sites for the binding of a third viral glycoprotein, gD, and for initiation of HSV-1 entry.
1,025 citations
"Heparan Sulfate Proteoglycans Are R..." refers background in this paper
...Further, even HSV-1 required 3-O sulfation but not 6-O-sulfation for infection (59)....
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...The specificity of binding to HSPGs resides mostly in the sulfation pattern of the attached HS chains (14, 59, 66)....
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TL;DR: Findings on the genetic organization and expression strategy of HEV suggest that it is the prototype human pathogen for a new class of RNA virus or perhaps a separate genus within the Caliciviridae family.
1,016 citations
"Heparan Sulfate Proteoglycans Are R..." refers background in this paper
...The viral genome consists of short 5 and 3 untranslated regions and three open reading frames (ORFs), called ORF1, ORF2, and ORF3 (62)....
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...ORF1 encodes the nonstructural proteins that are involved in virus replication and viral protein processing (1, 56), ORF2 encodes the viral capsid protein, and ORF3, which overlaps the 5 end of ORF2 (62), encodes a small protein shown to regulate the cellular environment (8, 29, 44)....
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