Biogenesis of JC polyomavirus associated extracellular vesicles

Morris‐Love, Jenna; O’Hara, Bethany A.; Gee, Gretchen V.; Dugan, Aisling S.; O’Rourke, Ryan; Armstead, Brandon E.; Assetta, Benedetta; Haley, Sheila A.; Atwood, Walter J.

doi:10.1002/jex2.43

Cited by 6 publications

(4 citation statements)

References 115 publications

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“…While this might be attributed to the cosedimentation of JCPyV particles and EVs following high-speed centrifugation, we do not rule out the possibility that JCPyV can propagate through EVs. Indeed, EV-mediated transfer of JCPyV has been reported in SVG-A (Morris-Love et al, 2019;Morris-Love et al, 2022) and choroid plexus epithelial cell cultures (O'Hara et al, 2020) and ex vivo through the association of JCPyV VP1 and genomic DNA with plasma derived EVs (Scribano et al, 2020). Similar to the observations made in our hiPSCderived astrocyte model, we found that JCPyV had a prominent impact on the proteomic content of the EV-enriched fraction from these infected cells.…”

Section: Discussionsupporting

confidence: 89%

“…Since EVs reflect the state of their cell-of-origin, they can serve as a rich source of information that can be leveraged for understanding molecular mechanisms at play in an inaccessible organ, such as the brain (Cheng & Hill, 2022). EVs have also been implicated in JCPyV propagation, as shown in vitro in SVG-A cells (Morris-Love et al, 2019;Morris-Love et al, 2022) and human choroid plexus epithelial cells (O'Hara et al, 2020) and ex vivo through the association of viral DNA and structural protein, VP1, with plasma derived EVs (Scribano et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Comprehensive proteomic analysis of JC polyomavirus-infected human astrocytes and their excreted vesicles

Oberholster

Mathias

Perriot

et al. 2023

Preprint

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JC polyomavirus (JCPyV) is the causative agent of progressive multifocal leukoencephalopathy (PML), a severe, and often fatal, demyelinating disease of the central nervous system. While PML has traditionally been characterized as a lytic infection of oligodendrocytes, more recent findings suggest an important role for astrocytes during the initial stages of disease. Here, using human induced pluripotent stem cell-derived astrocytes coupled with a multiparametric approach, we show that astrocytes are readily infected with JCPyV that strongly impacts their biology, inducing a unique proteomic signature. Furthermore, the changes observed mirror elements of ex vivo findings in PML brain lesions, including dysregulation of the cell cycle and activation of the DNA damage response. We also demonstrate that this signature is extended to extracellular vesicles (EVs) while being strikingly different from that of inflammatory conditions. Thus, our results support the relevance of using brain-derived EVs as a means to gain mechanistic insights into JCPyV pathophysiology in the brain and pave the way towards the identification of new biomarkers for the early stratification of patients at risk of developing PML.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Comprehensive proteomic analysis of JC polyomavirus-infected human astrocytes and their excreted vesicles

Oberholster

Mathias

Perriot

et al. 2023

Preprint

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“…In fact, it seemed the full complement of ESCRT proteins did more to control JCPyV infection. Finally, it was noted that depletion of single proteins from any pathway did not alter virus-EV spatial relationships or size distribution of released EVs [172]. It is crucial to recognize that despite the current findings across the literature, many of these proteins may act across multiple EV biogenesis and secretion pathways.…”

Section: Virus-ev Biogenesis Pathwaysmentioning

confidence: 94%

“…Knockdown of CD9 or CD81 similarly reduced viral spread, decreased EV-mediated infection, but internalization by target cells was unaffected. Knockdown of RAB8A, RAB27A, or GRASP65 reduced viral spread and decreased infectious EV production without differential uptake compared to controls, suggesting secreted autophagosomes contribute to the JCPyV(+) EV population [172]. Figure 5 outlines the proteins and their associated EV pathway.…”

Section: Virus-ev Biogenesis Pathwaysmentioning

confidence: 99%

Complexities of JC Polyomavirus Receptor-Dependent and -Independent Mechanisms of Infection

Morris‐Love

Atwood

2022

Viruses

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JC polyomavirus (JCPyV) is a small non-enveloped virus that establishes lifelong, persistent infection in most of the adult population. Immune-competent patients are generally asymptomatic, but immune-compromised and immune-suppressed patients are at risk for the neurodegenerative disease progressive multifocal leukoencephalopathy (PML). Studies with purified JCPyV found it undergoes receptor-dependent infectious entry requiring both lactoseries tetrasaccharide C (LSTc) attachment and 5-hydroxytryptamine type 2 entry receptors. Subsequent work discovered the major targets of JCPyV infection in the central nervous system (oligodendrocytes and astrocytes) do not express the required attachment receptor at detectable levels, virus could not bind these cells in tissue sections, and viral quasi-species harboring recurrent mutations in the binding pocket for attachment. While several research groups found evidence JCPyV can use novel receptors for infection, it was also discovered that extracellular vesicles (EVs) can mediate receptor independent JCPyV infection. Recent work also found JCPyV associated EVs include both exosomes and secretory autophagosomes. EVs effectively present a means of immune evasion and increased tissue tropism that complicates viral studies and anti-viral therapeutics. This review focuses on JCPyV infection mechanisms and EV associated and outlines key areas of study necessary to understand the interplay between virus and extracellular vesicles.

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Comprehensive proteomic analysis of JC polyomavirus-infected human astrocytes and their extracellular vesicles

Oberholster,

Mathias,

Perriot

et al. 2023

Microbiol Spectr

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JC polyomavirus (JCPyV) is an opportunistic virus that remains in a latent state in the kidneys and lymphoid organs of more than half of the human adult population. In rare cases of severe immune suppression, the virus is able to establish a lytic infection of glial cells in the brain, resulting in a debilitating, demyelinating disease known as progressive multifocal leukoencephalopathy (PML). Because of the exceptional species and tissue specificity of the virus, appropriate models of JCPyV infection in the brain are lacking, thus hampering progress toward the development of novel antiviral strategies and biomarkers of disease activity. While PML has traditionally been characterized as a lytic infection of oligodendrocytes, more recent findings suggest an important role for astrocytes during the initial stages of disease. Here, using human-induced pluripotent stem cell (hiPSC)-derived astrocytes coupled with a multiparametric approach, we show that (i) JCPyV readily infects and replicates in astrocytes, (ii) JCPyV strongly dysregulates the cell biology, and (iii) these results adequately reflect ex vivo findings. We perform an in-depth characterization of the effect of JCPyV on the cell proteome over time, demonstrating a strong dysregulation of the cell cycle and activation of the DNA damage response. Furthermore, we show that the proteomic signature observed for infected astrocytes is extended to extracellular vesicles, underlining their potential as a resource to gain valuable insights into JCPyV infection in the brain. IMPORTANCE Progressive multifocal leukoencephalopathy is a crimpling demyelinating disease of the central nervous system caused by JC polyomavirus (JCPyV). Much about JCPyV propagation in the brain remains obscure because of a lack of proper animal models to study the virus in the context of the disease, thus hampering efforts toward the development of new antiviral strategies. Here, having established a robust and representative model of JCPyV infection in human-induced pluripotent stem cell-derived astrocytes, we are able to fully characterize the effect of JCPyV on the biology of the cells and show that the proteomic signature observed for JCPyV-infected astrocytes is extended to extracellular vesicles (EVs). These data suggest that astrocyte-derived EVs found in body fluids might serve as a rich source of information relevant to JCPyV infection in the brain, opening avenues toward better understanding the pathogenesis of the virus and, ultimately, the identification of new antiviral targets.

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Biogenesis of JC polyomavirus associated extracellular vesicles

Cited by 6 publications

References 115 publications

Comprehensive proteomic analysis of JC polyomavirus-infected human astrocytes and their excreted vesicles

Comprehensive proteomic analysis of JC polyomavirus-infected human astrocytes and their excreted vesicles

Complexities of JC Polyomavirus Receptor-Dependent and -Independent Mechanisms of Infection

Comprehensive proteomic analysis of JC polyomavirus-infected human astrocytes and their extracellular vesicles

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