Infectious Entry and Neutralization of Pathogenic JC Polyomaviruses

Geoghegan, Eileen M.; Pastrana, Diana V.; Schowalter, Rachel M.; Ray, Upasana; Ho, Mitchell; Pauly, Gary T.; Sigano, Dina M.; Kaynor, Campbell; Cahir-McFarland, Ellen; Combaluzier, Benoît; Grimm, Jan; Buck, Christopher B.

doi:10.2139/ssrn.3155716

Cited by 5 publications

(8 citation statements)

References 62 publications

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“…MCPyV is the first human PyV clearly linked to the development of a specific cancer (12). Initial studies on the principal mechanism of infection confirmed the requirement of sulfated glycosaminoglycans for attachment and sialylated glycans for infectious uptake into host cells, which may, in fact, reflect a common mechanism for several PyV (28, 30, 31, 88). To extend our knowledge of the mechanism of initial infection, we addressed additional cellular requirements and routes of virus entry.…”

Section: Discussionmentioning

confidence: 98%

“…However, such GAG-induced conformational changes have no precedent among other PyVs. Of note, JC PyV can utilize two distinct pathways for infectious internalization, where one depends on interaction with sulfated GAGs and the other relies on sialic acid binding, this effect could depend on the host cell type (88). As the niche(s) for MCPyV infection remain only partially understood, the role of HSPGs in MCPyV entry may thus depend on specific cell types that are being infected in vivo.…”

Section: Discussionmentioning

confidence: 99%

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Infectious Entry of Merkel Cell Polyomavirus

Becker

Dominguez

Greune

et al. 2018

Preprint

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27Merkel Cell Polyomavirus (MCPyV) is a small, non-enveloped tumor virus associated 28 with an aggressive form of skin cancer, the Merkel cell carcinoma (MCC). MCPyV 29 infections are highly prevalent in the human population with MCPyV virions being 30 continuously shed from human skin. However, the precise host cell tropism(s) of 31MCPyV remains unclear: MCPyV is able to replicate within a subset of dermal 32fibroblasts, but MCPyV DNA has also been detected in a variety of other tissues. 33However, MCPyV appears different from other polyomaviruses as it requires sulfated 34 polysaccharides such as heparan sulfates and/or chondroitin sulfates for initial 35 attachment. Like other polyomaviruses, MCPyV engages sialic acid as a (co-36 )receptor. To explore the infectious entry process of MCPyV, we analyzed the cell 37 biological determinants of MCPyV entry into A549 cells, a highly transducible lung 38 carcinoma cell line, in comparison to well-studied simian virus 40 and a number of 39 other viruses. Our results indicate that MCPyV enters cells via caveolar/lipid raft-40 mediated endocytosis but not macropinocytosis, clathrin-mediated endocytosis or 41 glycosphingolipid-enriched carriers. The viruses internalized in small endocytic pits 42 that led the virus to endosomes and from there to the endoplasmic reticulum (ER). 43Similar to other polyomaviruses, trafficking required microtubular transport, 44 acidification of endosomes, and a functional redox environment. To our surprise, the 45 virus was found to acquire a membrane envelope within endosomes, a phenomenon 46 not reported for other viruses. Only minor amounts of viruses reached the ER, while 47 the majority was retained in endosomal compartments suggesting that endosome-to-48 ER trafficking is a bottleneck during infectious entry. 49 50 51 52 3 Importance 53 MCPyV is the first polyomavirus directly implicated in the development of an 54 aggressive human cancer, the Merkel Cell Carcinoma (MCC). Although MCPyV is 55 constantly shed from healthy skin, MCC incidence increases among aging and 56 immunocompromised individuals. To date, the events connecting initial MCPyV 57 infection and subsequent transformation still remain elusive. MCPyV differs from 58 other known polyomaviruses concerning its cell tropism, entry receptor requirements, 59 and infection kinetics. In this study, we examined the cellular requirements for 60 endocytic entry as well as the subcellular localization of incoming virus particles. A 61 thorough understanding of the determinants of the infectious entry pathway and the 62 specific biological niche will benefit prevention of virus-derived cancers such as 63 MCC. 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 Polyomaviruses (PyV) are small, non-enveloped dsDNA viruses with a diameter of 80 45-50 nm. The icosahedral (T=7) capids consist of 72 homopentameric capsomers of 81 the major capid protein VP1 with minor capsid proteins VP2/VP3 located within a 82 cavity underneath the VP1 pentamers. The PyV capsid harbors a chromatinized, 83 circu...

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Infectious Entry of Merkel Cell Polyomavirus

Becker

Dominguez

Greune

et al. 2018

Preprint

Self Cite

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“…Experiments with wild-type BKV and a BKV-VP1 Phe76Trp constructed mutant showed the same results. When the GM1 receptor is unavailable, GAGs are used as alternative receptors for SV40 infection in some cell types [175]. These findings provide a better understanding of virus evolution and a switch of receptor-binding specificity that trigger alteration of virus tissue/cell tropism and virus pathology, an understanding that is critical for diagnosis and treatment.…”

Section: Polyomaviridaementioning

confidence: 99%

“…Viruses can rapidly adapt to their environment. Although polyomaviruses are circular dsDNA viruses using host polymerases for transcription and replication, progressive multifocal leukoencephalopathy (PML)-mutant strains of JCPyV have been detected with VP1 mutations near the apical Sia-binding pocket, possibly resulting from positive selection during the PML development [175]. Complete blockage of the attachment of PML-mutant virus-like particles and partial reduction of binding of wild-type JCPyV genotypes 2 to either SFT cells (gliosarcoma cells with the SV40 large T antigen) or ART cells (ovarian cancer cells with the SV40 large T antigen) by heparin and HS20, which are GAGs, were observed.…”

Section: Polyomaviridaementioning

confidence: 99%

Sialoglycovirology of Lectins: Sialyl Glycan Binding of Enveloped and Non-enveloped Viruses

Sriwilaijaroen

Suzuki

2020

Methods in Molecular Biology

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On the cell sur "face", sialoglycoconjugates act as receptionists that have an important role in the first step of various cellular processes that bridge communication between the cell and its environment. Loss of Sia production can cause the developmental of defects and lethality in most animals; hence, animal cells are less prone to evolution of resistance to interactions by rapidly evolved Sia-binding viruses. Obligative intracellular viruses mostly have rapid evolution that allows escape from host immunity, leading to an epidemic variant, and that allows emergence of a novel strain, occasionally leading to pandemics that cause healthsocial-economic problems. Recently, much attention has been given to the mutual recognition systems via sialosugar chains between viruses and their host cells and there has been rapid growth of the research field "sialoglycovirology." In this chapter, the structural diversity of sialoglycoconjugates is overviewed, and enveloped and non-enveloped viruses that bind to Sia are reviewed. Also, interactions of viral lectins-host Sia receptors, which determine viral transmission, host range, and pathogenesis, are presented. The future direction of new therapeutic routes targeting viral lectins, development of easy-to-use detection methods for diagnosis and monitoring changes in virus binding specificity, and challenges in the development of suitable viruses to use in virus-based therapies for genetic disorders and cancer are discussed.

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“…These include α2,3‐ and α2,6‐containing sialic acid receptors including the α2,6 sialic acid‐containing glycan motif called lactoseries tetrasaccharide c (LSTc) 5,7–10 . The asilo ganglioside GM1 has also been reported as a receptor for some strains of JCPyV and recent studies have also demonstrated that JCPyV can utilize glucosoaminoglycans as cellular receptors 11,12 . It is currently unclear how engagement of these different receptors may affect the intracellular transport of JCPyV virions.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of JC polyomavirus infectivity by the retrograde transport inhibitor Retro‐2.1

Treasure

Nelson

2020

Microbiology and Immunology

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JC polyomavirus (JCPyV) is a common human pathogen that results in a chronic asymptomatic infection in healthy adults. Under conditions of immunosuppression, JCPyV spreads to the central nervous system and can cause the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML), a disease for which there are no vaccines or antiviral therapies. Retro-2 is a previously identified small molecule inhibitor that was originally shown to block retrograde transport of toxins such as ricin toxin from endosomes to the Golgi apparatus and endoplasmic reticulum (ER), and Retro-2.1 is a chemical analog of Retro-2 that has been shown to inhibit ricin intoxication of cells at low nanomolar concentrations. Retro-2 has previously been shown to prevent retrograde transport of JCPyV virions to the ER, but the effect of Retro-2.1 on JCPyV infectivity is unknown. Here it is shown that Retro-2.1 inhibits JCPyV with an EC 50 of 3.9 μM. This molecule inhibits JCPyV infection at dosages that are not toxic to human tissue culture cells. Retro-2.1 was also tested against two other polyomaviruses, the human BK polyomavirus and simian virus 40, and was also shown to inhibit infection at similar concentrations. Viral uncoating studies demonstrate that Retro-2.1 inhibits BKPyV infectivity in a manner similar to Retro-2. These studies demonstrate that improved analogs of Retro-2 can inhibit infection at lower dosages than Retro-2 and further optimization of these compounds may lead to effective treatment options for those suffering from JCPyV infection and PML.

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Infectious Entry and Neutralization of Pathogenic JC Polyomaviruses

Cited by 5 publications

References 62 publications

Infectious Entry of Merkel Cell Polyomavirus

Infectious Entry of Merkel Cell Polyomavirus

Sialoglycovirology of Lectins: Sialyl Glycan Binding of Enveloped and Non-enveloped Viruses

Inhibition of JC polyomavirus infectivity by the retrograde transport inhibitor Retro‐2.1

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