title: JC Polyomavirus Infection of Primary Human Renal Epithelial Cells Is Controlled by a Type I IFN-Induced Response.
abstract: The JC and BK human polyomaviruses (JCPyV and BKPyV, respectively) establish lifelong persistent infections in the kidney. In immunosuppressed individuals, JCPyV causes progressive multifocal leukoencephalopathy (PML), a fatal neurodegenerative disease, and BKPyV causes polyomavirus-associated nephropathy (PVN). In this study, we compared JCPyV and BKPyV infections in primary human renal proximal tubule epithelial (HRPTE) cells. JCPyV established a persistent infection, but BKPyV killed the cells in 15 days. To identify the cellular factors responsible for controlling JCPyV infection and promoting viral persistence, we profiled the transcriptomes of JCPyV- and BKPyV-infected cells at several time points postinfection. We found that infection with both viruses induced interferon production but that interferon-stimulated genes (ISGs) were only activated in the JCPyV-infected cells. Phosphorylated STAT1 and IRF9, which are responsible for inducing ISGs, translocated to the nucleus of JCPyV-infected cells but did not in BKPyV-infected cells. In BKPyV-infected cells, two critical suppressors of cytokine signaling, SOCS3 and SOCS1, were induced. Infection with BKPyV but not JCPyV caused reorganization of PML bodies that are associated with inactivating antiviral responses. Blockade of the interferon receptor and neutralization of soluble interferon alpha (IFN-α) and IFN-β partially alleviated the block to JCPyV infection, leading to enhanced infectivity. Our results show that a type I IFN response contributes to the establishment of persistent infection by JCPyV in HRPTE cells.
  
  
  
  The human polyomaviruses JCPyV and BKPyV both establish lifelong persistent infection in the kidneys. In immunosuppressed patients, BKPyV causes significant pathology in the kidney, but JCPyV is only rarely associated with disease in this organ. The reasons behind this striking difference in kidney pathology are unknown. In this study, we show that infection of primary human renal tubule epithelial cells with JCPyV and BKPyV results in divergent innate immune responses that control JCPyV but fail to control BKPyV. This is the first study that directly compares JCPyV and BKPyV infection in vitro in the same cell type they naturally infect, and the significant differences that have been uncovered could in part explain the distinct disease outcomes.
authors.affiliation: Graduate Program in Pathobiology, Brown University, Providence, Rhode Island, USA Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USA.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Assetta
authors.affiliation: Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: De Cecco
authors.affiliation: Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USA.
authors.forename: Bethany
authors.initials: B
authors.lastname: O'Hara
authors.affiliation: Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USA Walter_Atwood@brown.edu.
authors.forename: Walter J
authors.identifier: 0000-0002-3763-9073
authors.initials: WJ
authors.lastname: Atwood
mesh_terms: D001739:BK Virus / Q000276:immunology* / Q000502:physiology*; D002467:Cell Nucleus / Q000737:chemistry; D002470:Cell Survival; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000276:immunology* / Q000821:virology; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000378:metabolism; D007577:JC Virus / Q000276:immunology* / Q000502:physiology*; D021381:Protein Transport; D050794:STAT1 Transcription Factor / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism; D017735:Virus Latency
chemical_list: C494227:IRF9 protein, human; D007370:Interferon Type I; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein