Ganglioside GT1b Is a Putative Host Cell Receptor for the Merkel Cell Polyomavirus

Department of Molecular, Cellular, and Developmental Biology, University of Colorado at Boulder, 347 UCB, Boulder, CO 80309, USA.
Journal of Virology (Impact Factor: 4.44). 08/2009; 83(19):10275-9. DOI: 10.1128/JVI.00949-09
Source: PubMed


The Merkel cell polyomavirus (MCPyV) was identified recently in human Merkel cell carcinomas, an aggressive neuroendocrine skin cancer. Here, we identify a putative host cell receptor for MCPyV. We found that recombinant MCPyV VP1 pentameric capsomeres both hemagglutinated sheep red blood cells and interacted with ganglioside GT1b in a sucrose gradient flotation assay. Structural differences between the analyzed gangliosides suggest that MCPyV VP1 likely interacts with sialic acids on both branches of the GT1b carbohydrate chain. Identification of a potential host cell receptor for MCPyV will aid in the elucidation of its entry mechanism and pathophysiology.

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Available from: Kimberly D. Erickson, Oct 13, 2014
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    • "The most common recognition module is NeuAc; in addition, NeuGc and 9-O-acetylated sialic acids are also well-known receptors (28, 29). Examples of viral pathogens recognizing gangliosides are the influenza virus (30), simian virus 40 (SV40) (31), and polyomavirus (32, 33). Bacteria interact with gangliosides via toxins and adhesins, with the cholera toxin (34) and the Sialic-acid binding adhesin from the Class 1 carcinogen Helicobacter pylori, SabA (35, 36), being prominent examples. "
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    ABSTRACT: Gangliosides are sialic-acid-containing glycosphingolipids expressed on all vertebrate cells. They are primarily positioned in the plasma membrane with the ceramide part anchored in the membrane and the glycan part exposed on the surface of the cell. These lipids have highly diverse structures, not the least with respect to their carbohydrate chains, with N-acetylneuraminic acid (NeuAc) and N-glycolylneuraminic acid (NeuGc) being the two most common sialic-acid residues in mammalian cells. Generally, human healthy tissue is deficient in NeuGc, but this molecule is expressed in tumors and in human fetal tissues, and was hence classified as an onco-fetal antigen. Gangliosides perform important functions through carbohydrate-specific interactions with proteins, for example, as receptors in cell-cell recognition, which can be exploited by viruses and other pathogens, and also by regulating signaling proteins, such as the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR), through lateral interaction in the membrane. Through both mechanisms, tumor-associated gangliosides may affect malignant progression, which makes them attractive targets for cancer immunotherapies. In this review, we describe how proteins recognize gangliosides, focusing on the molecular recognition of gangliosides associated with cancer immunotherapy, and discuss the importance of these molecules in cancer research.
    Frontiers in Immunology 07/2014; 5:325. DOI:10.3389/fimmu.2014.00325
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    • "Linking a damage-associated molecular protein, calreticulin, to the LT-Ag in a DNA vaccine construct enhanced the generation of therapeutic CD8+ T cells [107]. Merkel cells and the majority of MCC express Ep-CAM, gangliosides, and MUC 1, which represent tumor-associated antigens currently being targeted via vaccine production and/or monoclonal antibody treatment strategies in other cancers [108,109,110,111,112]. Whether these will translate into effective treatment strategies for MCC remains to be determined. "
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    ABSTRACT: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer. The Merkel cell polyomavirus (MCPyV) is implicated in its pathogenesis. Immune mechanisms are also implicated. Patients who are immunosuppressed have an increased risk. There is evidence that high intratumoral T-cell counts and immune transcripts are associated with favorable survival. Spontaneous regressions implicate immune effector mechanisms. Immunogenicity is also supported by observation of autoimmune paraneoplastic syndromes. Case reports suggest that immune modulation, including reduction of immune suppression, can result in tumor regression. The relationships between MCPyV infection, the immune response, and clinical outcome, however, remain poorly understood. Circulating antibodies against MCPyV antigens are present in most individuals. MCPyV-reactive T cells have been detected in both MCC patients and control subjects. High intratumoral T-cell counts are also associated with favorable survival in MCPyV-negative MCC. That the immune system plays a central role in preventing and controlling MCC is supported by several observations. MCCs often develop, however, despite the presence of humoral and cellular immune responses. A better understanding on how MCPyV and MCC evade the immune response will be necessary to develop effective immunotherapies.
    Cancers 03/2013; 5(1):234-54. DOI:10.3390/cancers5010234
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    • "The authors demonstrated that purified MCPyV VP1 protein could assemble into pentamers, but not into virus-like particles. Such VP1 pentamers bound to liposomes containing ganglioside GT1b, but not GM1 (i.e., the receptor for SV40) or GD1a (i.e., the mouse polyomavirus receptor), while a very weak binding to GD1b (i.e., the receptor for BKV) was observed [72]. This result indicates that ganglioside GT1b is a putative receptor for MCPyV. "
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    ABSTRACT: Polyomaviruses are a family of small, nonenveloped viruses with a circular double-stranded DNA genome of ∼5,000 base pairs protected by an icosahedral protein structure. So far, members of this family have been identified in birds and mammals. Until 2006, BK virus (BKV), JC virus (JCV), and simian virus 40 (SV40) were the only polyomaviruses known to circulate in the human population. Their occurrence in individuals was mainly confirmed by PCR and the presence of virus-specific antibodies. Using the same methods, lymphotropic polyomavirus, originally isolated in monkeys, was recently shown to be present in healthy individuals although with much lower incidence than BKV, JCV, and SV40. The use of advanced high-throughput sequencing and improved rolling circle amplification techniques have identified the novel human polyomaviruses KI, WU, Merkel cell polyomavirus, HPyV6, HPyV7, trichodysplasia spinulosa-associated polyomavirus, and HPyV9. The skin tropism of human polyomaviruses and their dermatopathologic potentials are the focus of this paper.
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