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

ABSTRACT: JC polyomavirus (JCPyV) is the causative agent of progressive multifocal leukoencephalopathy (PML), a devastating demyelinating disease of the central nervous system that results in the widespread formation of lesions across the brain parenchyma. The virus is opportunistic and remains in a benign state in the kidneys and lymphoid organs of more than half of the global human adult population. However, in rare cases of severe or selective immune suppression, JCPyV can establish a lytic infection of glial cells in the brain. 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. Because of the exceptional species and tissue specificity of the virus, appropriate models of JCPyV infection in the brain are lacking, thus hampering progress towards the development of novel antiviral strategies and biomarkers of disease activity. Towards the aim of biomarker development extracellular vesicles (EVs) were isolated from JCPyV-infected and mock-infected human iPSC-derived astrocytes and analyzed by LC-MS/MS. As a inflammatory control, EVs were also isolated from cytokine-stimulated iPSC-derived astrocytes. We demonstrate that the proteomic signature associated with EVs from JCPyV-infected astrocytes reflect what was observed on a cellular level for infected astrocytes while being strikingly different from that of EVs generated under inflammatory conditions.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human) Jc Polyomavirus

TISSUE(S): Brain Macroglial Cell, Astroglial Cell

DISEASE(S): Progressive Multifocal Leukoencephalopathy

SUBMITTER: Larise Oberholster

LAB HEAD: Renaud A. Du Pasquier

PROVIDER: PXD044784 | Pride | 2023-08-28

REPOSITORIES: Pride

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Project description:Abstract: The Kaposi’s sarcoma-associated herpesvirus (KSHV) is an important oncogenic virus previously shown to be neurotropic, but studies on neuronal cells infection and pathogenesis are still very limited. Here we characterized the effects of KSHV infection on neuronal SH-SY5Y cells by the recombinant virus rKSHV219, which expresses both GFP and RFP to reflect latent and lytic phases of infection. We demonstrated that infected cells have a faster growth rate and the KSHV infection can be sustained. Interestingly, the infected cells can transition spontaneously back and forth between lytic and latent phases of infections, producing progeny viruses but without any adverse effects on cell growth. In addition, transcriptome analysis of viral and cellular genes in latent and lytic cells showed that unlike other infected cell lines, the latently infected cells expressed both latent and most, but not all the lytic genes required for infectious virion production. The uniquely expressed viral genes by the lytic cells were mainly involved in the early steps of virus binding. Some of the cellular genes that were deregulated in both latent and lytically infected cells are involved in cell adhesion, in cell signal pathways and tumorigenesis. The downregulated cellular CCDN1, PAX5, NFASC and upregulated CTGF, BMP4, YAP1, LEF1 and HLA-DRB1 genes were found to be associated with the cell adhesion molecules (CAM), hippo signaling and cancer. These deregulated genes may be involved in creating an environment that are unique in the neuronal cells to sustain cell growth upon KSHV infection not observed in other infected cell types. IMPORTANCE: Our study has provided evidence that the neuronal SH-SY5Y cells displayed unique cellular responses upon KSHV infection. Unlike other infected cells, this neuronal cell displayed a more rapid growth rate upon infection and can spontaneously transition back and forth between latent and lytic phases of infection. Unlike other latently infected cells, a number of lytic genes were also expressed in the latent phase of infection in addition to the established latent viral genes. They may play a role in deregulating a number of host genes that are involved in cell signaling and tumorigenesis in order to sustain the infection and growth advantages for the cells. Our study has provided novel insights on KSHV infection of neuronal cells and a potential new model for further studies to explore the underlying mechanism in viral and host interaction for neuronal cells, and the association of KSHV with neuronal diseases.

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

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