Mammalian Dengue Virus Receptors Arturo Cabrera-Hernandez and Duncan R. Smith! Molecular Pathology Laboratory, Institute of Molecular Biology and Genetics, Mahidol University, Salaya Campus, 25/25 Phuttamonthol Sai 4, Salaya, Nakorn Pathom, Thailand 73710
Abstract It has been estimated that some 3 billion people live in areas at the risk of infection with the dengue virus, and that up to 100 million infections occur each year, making dengue the most common arthropod-borne viral disease. Humans become infected following the bite of an infected mosquito, and infection can either be essentially without symptoms, or can result in severe, life-threatening manifestations. The initial interaction between a susceptible host cell and the dengue virus is a critical determinant of cell tropism and thus of pathogenicity. As such, considerable effort has been expended on trying to determine the nature of the initial cell: virus interaction and in particular to identify the nature of the receptor proteins used by dengue virus to enter into the cell. Over the last few years a number of proteins, including DC-SIGN, GRP-78, the 37/67kDa high-affinity laminin receptor and heat shock proteins 70 and 90, have all been implicated as dengue virus receptors in a number of cell types. In addition, the specific role of heparan sulfate in dengue virus binding and internalization of dengue still remains to be fully elucidated. This review seeks to provide an overview of the current state of research into mammalian dengue virus receptors, as an increased understanding of which molecules can function as dengue virus receptors and how their expression leads to cell susceptibility will potentially provide novel insights into the pathogenic mechanism of dengue virus infection. Keywords: 37/67kDa high-affinity laminin receptor, DC-SIGN, Fc receptor, flavivirus, GRP78, heparan sulfate, HSP70, HSP90, L-SIGN.
Introduction Approximately 100 million people are believed to be infected with the dengue virus each year, making it the most prevalent arthropodborne viral disease. While the majority of these infections are believed to be asymptomatic, the infection may result in a febrile disease termed dengue fever (DF) or it may result in haemorrhagic manifestations, which are classified as either dengue haemorrhagic fever (DHF) or dengue shock syndrome (DSS) dependent upon severity. Dengue virus is classified in the family Flaviviridae, genus
Flavivirus, and species dengue virus, and comprises of four antigenically distinct viruses termed DENV-1, DENV-2, DENV-3 and DENV4. The dengue viruses are enveloped positivesense single-stranded RNA viruses of approximately 11 kb that encodes for three structural proteins (core, pre-membrane and envelope) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5) in one open reading frame. The principal vectors of dengue virus transmission are Aedes aegypti and Aedes albopictus mosquitoes. The transmission of the
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dengue virus to humans occurs after the bite of an infected mosquito, and the subsequent ability of the virus to infect the host depends on the capacity of the virus to bind to, internalize into and productively infect target cells. The initial interaction between the dengue virus and host cells has been the focus of considerable efforts to isolate and characterize the molecules involved. As for other virus : cell systems, the initial dengue virus : cell interaction is believed to involve the concentration of dengue virus particle through an initial interaction with a low-affinity binding element before transfer to a second receptor protein able to bind and internalize the virus. In the last few years considerable insights into this mechanism have emerged, bringing with them the possibility of new strategies to stop dissemination of the virus, or to identify molecular markers linked to individuals at high risk of developing the severe forms of the disease.
The Role of Heparan Sulfate In 1997, Chen and colleagues identified the glycosaminoglycan molecule, heparan sulfate, as a non-specific receptor molecule responsible for dengue virus attachment in several cell lines. Heparan sulfate is expressed in almost all cells types, and is composed of alternating hexuronic acid / D-glucosamine disaccharides, which contain different degrees and patterns of sulfation, forming a linear chain with a remarkable diversity in length and structural complexity. This structural diversity confers the ability to recognize a vast array of ligands and to participate in a wide variety of physiological functions[6,7]. A number of viruses[8-19], bacteria and parasites [21-24] exploit the adhesive properties of heparan sulfate and use it as a binding molecule to attach to a target cell. The contribution of heparan sulfate expression to dengue virus entry has been 120
variously shown by (i) a significant decrease in dengue virus binding capacity after enzymatic removal of heparan sulfate[25-29]; (ii) a dose-dependent heparin binding inhibition[26,27,29,30-33]; and (iii) virus-binding assays in a mutant target cell lacking heparan sulfate expression[28,32]. In agreement with previous reports that showed a principal role of the dengue virus envelope protein in the initial binding to target cells[33,34], Chen and colleagues, delineated the participation of the envelope protein to domain III, and detected two potential consensus heparan sulfate binding motifs inside this domain (amino acids 284-310 and amino acids 386411). These observations were corroborated by studies that inhibited the binding and internalization of the dengue virus with monoclonal antibodies specific against this envelope protein region [35,36] or with recombinant soluble forms of envelope protein domain III. Detailed in vitro and in vivo competition binding assays using a synthetic undecapeptide based on the epitope region recognized by the anti-protein E neutralizing monoclonal antibody, 4E11, identified a highly conserved region in all four serotypes (amino acids 306-314), as essential to the interaction with heparin, a structural homologue of heparan sulfate; however, complementary roles for domains I and II cannot be excluded . By contrast, the particular structural motifs in the heparan sulfate molecule that participate in the binding remain to be clarified. Binding assays employing recombinant E protein and heparan sulfate homologues have shown a minimum length requirement of 10 disaccharides with a flexible structure of at least 39Å, and a highly sulfated state for optimal binding[5,38], while enzymatic analysis suggest the additional presence of b-linked terminal glucose, galactose or fucose as well as sialic acid residues may also be required. Studies using liver cell lines (HuH-7 and HepG2) have shown that the binding of the dengue virus Dengue Bulletin – Vol 29, 2005
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to liver cells is not saturatable[25,39] and in HuH7 cells this has been shown to be a consequence of heparan sulfate expression. In contrast, Vero and LLC-MK cells have both shown to be saturatable, although binding can still be blocked in a dose-dependent fashion by heparin  . The dengue virus binding differences between hepatoma and kidney cell lines could possibly be related to the high degree of sulfation reported for heparan sulfate in liver cell lines or in human liver cells that give liver cells a particularly high capacity for concentrating the virus at the membrane surface and could be related to the particular tropism of liver for dengue virus. Interestingly, heparin does not inhibit recombinant E protein or dengue virus binding to insect cell lines[26,32], suggesting that the target cell as well as the serotype may all influence the initial heparan sulfate-dengue virus binding interaction. Given the ubiquitous heparan sulfate expression at the membrane surface in almost all organs[6,7] but the restricted number of dengue virus-target organs, as well as the
divergence between the kinetics of dengue virus binding and dengue virus internalization and the observation that the elimination/reduction of heparan sulfate significantly decreases but does not abolish completely the binding and internalization of the dengue virus[25,27-29], several groups have proposed the existence of additional receptors participating in concert during the internalization process [27-30] . It has been proposed therefore that heparan sulfate serves to concentrate the virus at the membrane surface and facilitate interaction of the virus with a second, high-affinity receptor [4,41], although the direct participation of heparan sulfate-proteoglycans in virus binding and entry cannot be excluded. The identity of these high affinity receptor elements has been the object of considerable investigation, resulting in the identification of several characterized receptors as well as a number of potential candidate receptor proteins many of which have been identified by little more than a molecular mass. A summary of the known and potential dengue virus receptors is presented in the Table.
Table. Known and proposed dengue virus receptors in mammalian and insect cells
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Dengue Virus Receptors in Cells of the Myeloid Lineage Since the earliest reports implicating monocytes (MO) and macrophages (φ) in the pathogenesis of dengue infection[2,61], considerable effort has been undertaken to clarify their role during the course of the infection. MO/φ are a complex and heterogeneous population, derived from a common progenitor in bone marrow. As differentiation progresses, they migrate through the blood stream, finally distributing into the peripheral organs, where the particular microenvironment confers a distinctive macrophage’s characteristics resulting in different subsets of cells with specific characteristics and functions as well as conferring a specific susceptibility to dengue virus infection. Thus, in a primary infection, only 1% to 2% of blood MO/φ are infected, whereas monocyte-derived dendritic cells (DCs) are highly susceptible and are productively infected, as has been shown by both in vitro and in vivo studies[63,64]. In contrast, Kupffer cells and Langerhans cells, the macrophages residing in the liver and skin respectively, can be infected but the infection is non-productive[64,65]. Blood MO/φ were defined as the principal target cells infected during a second infection with a heterologous DENV infection, and infection was shown to occur via the antibodydependent enhancement (ADE) mechanism[61,66]. The participation of receptors that recognize the constant region of IgG, FcγRI and FcγRII[51,52] were identified as key players during the process of ADE through the internalization of the complex formed between the anti-dengue antibody, the dengue virus and the Fc receptor, when the antibodies are either cross-reacting but not neutralizing or when the antibodies are present at sub-neutralizing concentrations. Although important during the process of ADE, Fc receptors are not the 124
only dengue virus receptors expressed by macrophages. In one early work employing adherent human monocytes, Daughaday and colleagues  revealed the existence of receptors sensitive to trypsin, in addition to the trypsin insensitive Fc receptors. Subsequent work by Bielefeldt-Ohmann employing a virus overlay protein binding assay (VOPBA) to membrane proteins from the myelomonocytic cell line HL60 identified two dengue virusbinding non-Fc proteins of 40/45 and 70/75 kDa. Remarkably, although the competitive inhibitor heparin decreased the HL60-dengue virus binding capacity, the opposite effect was reported after the enzymatic removal of HS supporting the co-participation of HS and the high affinity receptor during the binding process. The identity of the high affinity receptor has remained elusive for several years, although several lines of research have revealed some clues about the identity of the receptor(s). Chen and colleagues detected a CD14-dependent-LPS-inhibition during dengue virus binding to primary human blood MO/φ, suggesting that one CD14-coupledunidentified molecule acted as a dengue virus receptor. Moreno-Altamirano and colleagues employing a DENV-2-bound Sepharose 4B column and VOPBA assays defined 4 proteins bands with molecular masses of 27, 45, 67 and 87 kDa on the cell surface of the primary human blood MO/φ, while in PMA-differentiated U-937 cells they detected only the 45 and 67 kDa bands whereas no bands were detected in undifferentiated U-937 cells. Interestingly, these results may support an earlier observation in which it was noted that there is an increase in the susceptibility to infection as the U-937 macrophage cell line differentiates  . Reyes del Valle and colleagues employing a combination of E protein column affinity chromatography and VOPBA assay analysed membrane extracts Dengue Bulletin – Vol 29, 2005
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from the U937 cell line and the human neuroblastoma cell line SK-SY-5Y and detected 5 proteins bands with molecular masses of 45, 60, 75, 84 and 100 kDa. Mass spectroscopy analysis identified the 84 kDa band as Heat Shock Protein 90 (HSP90). HSPs are a family of highly conserved molecular chaperones with a broad intra-cellular location that assist the structure formation of proteins in vivo and participate in a number of normal, stress and pathological responses. These properties are exploited by a number of different viruses to assist the correct folding and trafficking of viral proteins during the virus life cycle. In addition to their intra-cellular location, some family members are located at the cell surface, enclosed in detergentresistant microdomains (lipids rafts) where they participate in a variety of functions, including functioning as co-receptors for ligands or viruses [71,73] . Thus, Hsc70 and integrins αvβ3 and αxβ2 cluster during rotavirus binding, whereas GRP78, a HSP homolog, associates with the molecule MHCI and the integrin αvβ3 during coxsackievirus A9 (CAV-9) entry. Additionally, HSP90 and HSP70 are known to associate at the cell surface membrane, participating in LPS (lipopolysaccharide) binding in the so-called “CD14-independent LPS receptor cluster”. This observation, in the light of the LPSdependent- inhibition of DENV infection, permitted Reyes del Valle and colleagues to infer and subsequently demonstrate the coparticipation of the lipid raft-associated HSP70 during DENV entry to the cell. Prolonged expression of HSP70 and HSP90 has been detected in animals exposed to fever range hyperthermia , and fever is a common symptom of dengue infection. It is interesting to speculate therefore that the dengue viruses’ ability to use HSPs may result in a higher infection potential during the fever period. The idea that circulating MO/φ are the primary target during DENV infection changed Dengue Bulletin – Vol 29, 2005
after several groups reported the finding that DCs are highly susceptible to infection by the dengue virus[63,78-80]. This quickly led to the identification in immature human DCs of the dendritic cell-specific intercellular adhesion molecule grabbing non-integrin (DC-SIGN, CD209)[54,55] as a dengue virus non-Fc-receptor protein. DC-SIGN is a multifunctional protein involved in the establishment of the immunological synapse between the dendritic cells and T cells through binding to the ICAM3 protein, in the migration of DCs based on its ability to bind the ICAM-2 protein as well as in the binding and/or internalization of a variety of viruses [83-89] , bacteria [90-94] , parasites [90,95,96] , yeast  and fungus  . Interestingly, it was the ability of DC-SIGN to bind the HIV-1 envelope glycoprotein gp120 that originally led Curtis and colleagues to isolate, clone, sequence and study this C-type lectin protein in 1992. Using DC-SIGN-specific monoclonal antibodies, its expression has been detected in blood, particularly in one small subset of myeloid DC CD14+ cells , whereas in peripheral tissues its expression has been found in immature myeloid DCs in skin, intestine, lung, liver, placenta and lymph nodes[81,101,102]. Additionally, its presence has been reported in alveolar macrophages[98,103] but neither Langerhans cells nor plasmacytoid DCs express DC-SIGN[81,104]. The participation of DC-SIGN in dengue virus infections was shown by competition assays employing either monoclonal antibodies against DC-SIGN or soluble DC-SIGN to inhibit DENV infection, as well by the acquisition of susceptibility to dengue infection by a dengue virus-resistant cell line (THP-1) after DC-SIGN transfection [54,55]. However, mutations in the DC -SIGN internalization motifs as well as in its intracellular domain permit infection at levels similar to the wild type protein, suggesting that DC-SIGN may participate in the early events of virus attachment but function as a 125
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co-receptor during the internalization process. Based on immunohistochemical analysis, alveolar macrophages have been reported to be susceptible to infection by the dengue virus[105,106] and to express DC-SIGN, but the involvement of DC-SIGN in the infection process remains to be demonstrated. Attention has also focused on a homolog of DC-SIGN, called L-SIGN. While L-SIGN is a homolog of DC-SIGN, there are differences in the extracellular domain as well as differences in its ability to bind some ligands [108,109] and L-SIGN expression is apparently restricted to liver sinusoidal endothelial cells as well as a subset of endothelial cells in the paracortex zone of lymph nodes[101,110]. While L-SIGN has the ability to bind dengue viruses and its expression in THP-1 cells induces susceptibility to dengue virus infection, and specific antibodies against L-SIGN can subsequently block the acquired susceptibility, an in vivo role for this protein remains to be established. The L-SIGN-dependent DENV infection of THP-1 cells offers an intriguing possibility for the participation of L-SIGN in dengue virus infection in the liver, where the physical location of liver sinusoidal endothelial cells confers a strategic advantage for interacting with DENV in the early period of infection. Although an in vivo role for L-SIGN in dengue virus internalization has not been demonstrated, histochemical and in situ hybridization analysis of post-mortem samples have shown the presence of DENV antigen in the vascular endothelial liver cells, although the presence of dengue virus was reported to be negative[105,106]. However, it is possible that, as has been demonstrated for other viruses, the participation of L-SIGN could be limited to the binding, concentration and infection in trans- of neighbouring cells as has been shown to occur with the human immunodeficiency virus, hepatitis C virus and Ebola virus[84,110,112]. 126
Dengue Virus Receptors Expressed in the Liver Several lines of evidence show the involvement of the liver during dengue virus infections. Analyses of liver sections from fatal cases of dengue virus infection by immunohistochemistry consistently demonstrate the presence of dengue virus antigens in hepatocytes, Kupffer cells and/or liver endothelial cells[86, 105, 113], and the presence of the dengue virus RNA in hepatocytes and/or Kupffer cells has been demonstrated by RTPCR and in situ hybridization.[106,114-116] Increases in alanine transaminase (ALT) and aspartate transaminase (AST) levels during the development of the disease[117-121] as well as liver enlargement are common features of the disease. Although damage to the liver in the most severe forms of the disease has been well documented, it is not clear what the initial target cells are and what mediates the initial contact between the virus and the liver target cell. In the absence of a valid animal model system, and given the difficulties associated with working with primary human cells, studies of dengue virus infection of the human liver in vitro have primarily centred around the use of human hepatoma cell lines[25,29,31,39,48-50,120,123]. While it needs to be borne in mind that these cells possess considerable variation from primary human cells in that they have undergone neoplastic transformation[124,125,126], they evince many of the properties seen in patients during dengue virus infection such as increases in the level of ALT/AST, a rise in the production of the chemokine RANTES as well as virusinduced apoptosis[128-130]. However, at some point the use of human primary hepatoma cells will be required to validate the results generated with transformed cell lines. In 2000, Hilgard and Stockert, employing the human hepatoma cell line HuH-7, reported the participation of two 33 and 37-kDa trypsinDengue Bulletin – Vol 29, 2005
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sensitive heparan sulfate proteoglycans in the virus binding, attachment and internalization, but presented no further characterization of the molecules identified. However, in 2004, Thepparit and Smith, using a combination of virus overlay protein binding assay and mass spectroscopy, identified the 37/67-kDa highaffinity laminin receptor as a DENV-1 receptor expressed by HepG2 liver cells. Using a combination of the natural ligand for this receptor (soluble laminin) and antibodies directed against the 37/67kDa high-affinity laminin receptor, the authors further restricted the participation of this receptor to DENV-1. More recently, Tio et al., using a twodimensional VOPBA analysis of proteins expressed by Porcine kidney cell line PS Clone D, confirmed the ability of the 37/67-kDa highaffinity laminin receptor to bind DENV-1, and suggested that, in addition, the 37/67-kDa highaffinity laminin receptor under certain conditions may also be able to bind DENV-2 and DENV-3 (but not DENV-4). While Tio et al. suggest a broader role for the 37/67-kDa high-affinity laminin receptor as a dengue virus receptor, their use of porcine kidney cells as well as their observations relying solely on binding studies without validation of receptor function makes the results of questionable significance. The 37/67 kDa high-affinity laminin receptor is a nonintegrin cell surface receptor that mediates high-affinity interactions between cells and laminin. The 37kDa molecule is believed to be a precursor protein generating the mature 67kDa laminin receptor, with the maturation process involving dimerization and acylation of the precursor, although the relationship between the two forms is not fully understood. The 37/67kDa high-affinity laminin receptor is expressed in a number of normal tissues including liver cells, as well as being up-regulated in hepatocyte carcinoma cells. While the natural ligand for this receptor is the laminin protein in the extracellular matrix, some Dengue Bulletin – Vol 29, 2005
alphaviruses[134,135], the cellular prion protein and the cytotoxic necrotizing factor 1, a bacterial ligand, all use the 37/67 kDa highaffinity laminin receptor protein as receptor with pathological consequences for the host. Evidence also suggests that there is an association between the 37/67kDa high-affinity laminin receptor protein and other glycoproteins at the cell surface, including the dengue virus low-affinity binding molecule heparan sulfate. Thepparit and Smith  reported an additive effect on dengue virus internalization between heparan sulfate and the 37/67kDa high-affinity laminin receptor, suggesting a parallel with the mechanism of the cellular prion protein where binding has been shown to consist of a complex between heparan sulfate, the 37/67kDa high-affinity laminin receptor and the prion protein. However, given that the 37/67kDa high-affinity laminin receptor protein is expressed in a number of cell types while only a few of them are documented to be able to be infected by the dengue virus, it is likely that additional elements of this receptor system remain to be determined. Additionally in 2004, Jindadamrongwech and Smith, employing VOPBA on membrane extracts of the human hepatoma cell line HepG2, identified dengue-binding proteins with approximate molecular masses of 78-80, 90, 98 and 102kDa for DENV-2, 90, 130 and 182kDa for DENV-3 and 90 and 130kDa for DENV-4. Further coupling VOPBA and mass spectroscopy, they subsequently identified the 78kDa band for DENV-2 as the glucose-related protein, GRP78 (BiP). Pre-treatment with anti-GRP78 antibodies resulted in either a partial inhibition of DENV-2 infection or a dosedependent virus production enhancement dependent upon the specific antibody used, suggesting that additional receptor elements are almost certainly required. GRP78 is a homolog of the HSP proteins and is located principally in the endoplasmic reticulum (ER) 127
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where it may function to assist correct protein folding. The presence of GRP78 at the cell surface has been demonstrated, where it can function as co-receptor for CAV-9 binding and as the activated and receptor recognized form of α2-macroglobulin signalling receptor. Given that GRP78 is a homolog of HSPs, it is possible that other members of this stress-induced family may play a role in dengue virus binding and internalization in different cell types.
Future Directions While the last few years have shown significant progress being made in determining the nature and mechanism of the actions of the dengue virus receptor proteins, many questions still remain to be answered. Future research will need to define more closely which specific cell types are susceptible to both productive and non-productive infection as well as defining what receptors are expressed by those cells. The issue of serotype-specific usage of receptors as noted with some of the liver cell lines remains
controversial, and studies with human primary cells are urgently needed. The question of the biological significance of receptor usage is one that will become particularly prominent. In this regard, the recent work by Sakuntabhai and co-authors, who reported a promoter polymorphism in CD209 (DC-SIGN) that provides significant protection against dengue fever but not against dengue haemorrhagic fever, is particularly important. The identification of this and other receptors may open the way to the development of specific, receptor-based prophylaxis and therapy as well as, potentially, the early genetic identification of individuals at increased risk of developing dengue fever or, more importantly, dengue haemorrhagic fever or dengue shock syndrome.
Acknowledgements Arturo Cabrera-Hernandez is supported by the Consejo Nacional de Ciencia y Tecnología, México, and Duncan R. Smith is supported by the Thailand Research Fund and Mahidol University, Thailand.
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