Genetic and Functional Dissection of the Role of Individual 5-HT2 Receptors as Entry Receptors for JC Polyomavirus

Assetta, Benedetta; Morris‐Love, Jenna; Gee, Gretchen V.; Atkinson, Abigail L.; O’Hara, Bethany A.; Maginnis, Melissa S.; Haley, Sheila A.; Atwood, Walter J.

doi:10.1016/j.celrep.2019.04.067

Cited by 22 publications

(17 citation statements)

References 32 publications

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“…Cell culture models using purified JCPyV virions have shown that the virus requires the sialic acid-containing attachment receptor, lactoseries tetrasaccharide C (LSTc), to bind target cells [12][13][14][15]. The virus then uses one of at least three isoforms of serotonin receptor to enter the cells by clathrin dependent mechanisms [13,14,16]. In human tissue sections both the attachment receptor and the entry receptors are expressed on human kidney tubule epithelial cells and on choroid plexus epithelial cells and virus binds to these cells in a sialic acid dependent manner [17].…”

Section: Introductionmentioning

confidence: 99%

JC Virus infected choroid plexus epithelial cells produce extracellular vesicles that infect glial cells independently of the virus attachment receptor

et al. 2020

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The human polyomavirus, JCPyV, is the causative agent of progressive multifocal leukoencephalopathy (PML) in immunosuppressed and immunomodulated patients. Initial infection with JCPyV is common and the virus establishes a long-term persistent infection in the urogenital system of 50-70% of the human population worldwide. A major gap in the field is that we do not know how the virus traffics from the periphery to the brain to cause disease. Our recent discovery that human choroid plexus epithelial cells are fully susceptible to virus infection together with reports of JCPyV infection of choroid plexus in vivo has led us to hypothesize that the choroid plexus plays a fundamental role in this process. The choroid plexus is known to relay information between the blood and the brain by the release of extracellular vesicles. This is particularly important because human macroglia (oligodendrocytes and astrocytes), the major targets of virus infection in the central nervous system (CNS), do not express the known attachment receptors for the virus and do not bind virus in human tissue sections. In this report we show that JCPyV infected choroid plexus epithelial cells produce extracellular vesicles that contain JCPyV and readily transmit the infection to human glial cells. Transmission of the virus by extracellular vesicles is independent of the known virus attachment receptors and is not neutralized by antisera directed at the virus. We also show that extracellular vesicles containing virus are taken into target glial cells by both clathrin dependent endocytosis and macropinocytosis. Our data support the hypothesis that the choroid plexus plays a fundamental role in the dissemination of virus to brain parenchyma.

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Section: Introductionmentioning

confidence: 99%

JC Virus infected choroid plexus epithelial cells produce extracellular vesicles that infect glial cells independently of the virus attachment receptor

et al. 2020

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“…In addition, sites of JCPyV infection are consistent with expression patterns of 5-HT 2 Rs, including expression in kidney and glial cells [ 126 , 127 , 128 ]. In further support, the recent literature has indicated an interaction between 5-HT 2 Rs and JCPyV through the utilization of a PLA assay [ 129 ]. In this report interactions were found to occur as early as 5 min postinfection but were transient, dissipating at 15 min postinternalization [ 129 ].…”

Section: Entrymentioning

confidence: 83%

“…In further support, the recent literature has indicated an interaction between 5-HT 2 Rs and JCPyV through the utilization of a PLA assay [ 129 ]. In this report interactions were found to occur as early as 5 min postinfection but were transient, dissipating at 15 min postinternalization [ 129 ]. It is thought that the difference in internalization strategy usurped by JCPyV in comparison to other polyomaviruses is due to JCPyV requiring the additional proteinaceous cellular receptor for mediating viral internalization, 5-HT 2 Rs, though this remains unconfirmed though experimentation.…”

Section: Entrymentioning

confidence: 83%

“…The determination that JCPyV likely uses CME for internalization was further supported by the finding that JCPyV entry was sensitive to siRNA targeting the heavy chain of clathrin, and JCPyV localizes with clathrin at time points consistent with viral internalization [ 111 ]. Interestingly, JCPyV internalization also relies on the endocytic protein β-arrestin, the first association of this protein with the promotion of virus entry [ 111 , 129 ]. β-arrestin binding domains within the 5-HT 2 R family, the Ala-Ser-Lys (ASK) motif as well as a proline, separated by six residues from a Asp-Arg-Tyr (DRY) motif on the third intracellular loop of 5-HT 2 Rs [ 130 , 131 , 132 , 133 ], have been demonstrated to be important for JCPyV internalization and infection [ 111 , 129 ].…”

Section: Entrymentioning

confidence: 99%

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Taking the Scenic Route: Polyomaviruses Utilize Multiple Pathways to Reach the Same Destination

Mayberry

Maginnis

2020

Viruses

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Members of the Polyomaviridae family differ in their host range, pathogenesis, and disease severity. To date, some of the most studied polyomaviruses include human JC, BK, and Merkel cell polyomavirus and non-human subspecies murine and simian virus 40 (SV40) polyomavirus. Although dichotomies in host range and pathogenesis exist, overlapping features of the infectious cycle illuminate the similarities within this virus family. Of particular interest to human health, JC, BK, and Merkel cell polyomavirus have all been linked to critical, often fatal, illnesses, emphasizing the importance of understanding the underlying viral infections that result in the onset of these diseases. As there are significant overlaps in the capacity of polyomaviruses to cause disease in their respective hosts, recent advancements in characterizing the infectious life cycle of non-human murine and SV40 polyomaviruses are key to understanding diseases caused by their human counterparts. This review focuses on the molecular mechanisms by which different polyomaviruses hijack cellular processes to attach to host cells, internalize, traffic within the cytoplasm, and disassemble within the endoplasmic reticulum (ER), prior to delivery to the nucleus for viral replication. Unraveling the fundamental processes that facilitate polyomavirus infection provides deeper insight into the conserved mechanisms of the infectious process shared within this virus family, while also highlighting critical unique viral features.

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“…This has been linked to alterations in the protein kinase A (PKA) pathway which interfered with claudin 1, an important receptor for post-binding steps of hepatitis C virus cell entry (17,49). For JC polyomavirus, 5-HT2 receptor antagonists inhibited infection due to interference of binding of β-arrestin to the 5-HT2A receptors, which is required for internalization of the virus via clathrin-coated vesicles (20,51,52). During reovirus infection, 5-NT strongly inhibited the cell entry of reovirus whereas MM enhanced reovirus infectivity.…”

Section: Addition Of 5-nt To Cells Led To a Stark Reduction In The Numentioning

confidence: 99%

Serotonergic drugs inhibit CHIKV infection at different stages of the cell entry pathway

Bouma

Pol

Sanders

et al. 2020

Preprint

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AbstractChikungunya virus (CHIKV) is an important re-emerging human pathogen transmitted by mosquitoes. The virus causes an acute febrile illness, chikungunya fever, which is characterized by headache, rash and debilitating (poly)arthralgia that can reside for months to years after infection. Currently, effective antiviral therapies and vaccines are lacking. Due to the high morbidity and economic burden in the countries affected by CHIKV, there is a strong need for new strategies to inhibit CHIKV replication. The serotonergic drug, 5-nonyloxytryptamine (5-NT), was previously identified as a potential host-directed inhibitor for CHIKV infection. In this study, we determined the mechanism of action by which the serotonin receptor agonist 5-NT controls CHIKV infection. Using time-of-addition and entry bypass assays we found that 5-NT predominantly inhibits CHIKV in the early phases of the replication cycle; at a step prior to RNA translation and genome replication. Intriguingly, however, no effect was seen during virus-cell binding, internalization, membrane fusion and gRNA release into the cell cytosol. Additionally, we show that the serotonin receptor antagonist MM also has antiviral properties towards CHIKV and specifically interferes with the cell entry process and/or membrane fusion. Taken together, pharmacological targeting of 5-HT receptors may represent a potent way to limit viral spread and disease severity.ImportanceThe rapid spread of mosquito-borne viral diseases in humans puts a huge economic burden on developing countries. For many of these infections, including Chikungunya virus (CHIKV), there are no specific treatment possibilities to alleviate disease symptoms. Understanding the virus:host interactions that are involved in the viral replication cycle is imperative for the rational design of therapeutic strategies. In this study, we discovered an antiviral compound and elucidated the mechanism of action and propose serotonergic drugs as potential host-directed antivirals for CHIKV.

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Genetic and Functional Dissection of the Role of Individual 5-HT2 Receptors as Entry Receptors for JC Polyomavirus

Cited by 22 publications

References 32 publications

JC Virus infected choroid plexus epithelial cells produce extracellular vesicles that infect glial cells independently of the virus attachment receptor

JC Virus infected choroid plexus epithelial cells produce extracellular vesicles that infect glial cells independently of the virus attachment receptor

Taking the Scenic Route: Polyomaviruses Utilize Multiple Pathways to Reach the Same Destination

Serotonergic drugs inhibit CHIKV infection at different stages of the cell entry pathway

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