title: Immune suppression of JC virus gene expression is mediated by SRSF1.
abstract: Progressive multifocal leukoemcephalopathy (PML) is a fatal demyelinating disease caused by the human neurotropic JC virus (JCV). JCV infects the majority of the human population during childhood and establishes a latent/persistent life-long infection. The virus reactivates under immunosuppressive conditions by unknown mechanisms, resulting in productive infection of oligodendrocytes in the central nervous system (CNS). Given the fact that the natural occurrence of PML is strongly associated with immunosuppression, the functional and molecular interaction between glial cells and neuroimmune signaling mediated by soluble immune mediators is likely to play a major role in reactivation of JCV and the progression of the lytic viral life cycle leading to the development of PML. In order to explore the effect of soluble immune mediators secreted by peripheral blood mononuclear cells (PBMCs) on JCV transcription, primary human fetal glial (PHFG) cells were treated with conditioned media from PBMCs. We observed a strong suppression of JCV early as well as late gene transcription in cells treated with conditioned media from induced PBMCs. Using a variety of virological and molecular biological approaches, we demonstrate that immune mediators secreted by PBMCs induce the expression of SRSF1, a strong inhibitor of JCV gene expression, and inhibit the replication of JCV. Our results show that downregulation of SRSF1 in glial cells overcomes the suppression of JCV gene expression and its replication mediated by soluble immune mediators. These findings suggest the presence of a novel immune signaling pathway between glial cells and PBMCs that may control JCV gene expression during the course of viral reactivation.
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Temple University Lewis Katz School of Medicine, 3500 North Broad Street, 7th Floor, Philadelphia, PA, 19140, USA.
authors.forename: Rahsan
authors.initials: R
authors.lastname: Sariyer
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Temple University Lewis Katz School of Medicine, 3500 North Broad Street, 7th Floor, Philadelphia, PA, 19140, USA.
authors.forename: Francesca Isabella
authors.initials: FI
authors.lastname: De-Simone
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Temple University Lewis Katz School of Medicine, 3500 North Broad Street, 7th Floor, Philadelphia, PA, 19140, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gordon
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Temple University Lewis Katz School of Medicine, 3500 North Broad Street, 7th Floor, Philadelphia, PA, 19140, USA. isariyer@temple.edu.
authors.forename: Ilker Kudret
authors.initials: IK
authors.lastname: Sariyer
mesh_terms: D017077:Culture Media, Conditioned / Q000494:pharmacology*; D005333:Fetus; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D007577:JC Virus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D017077:Culture Media, Conditioned; D034741:RNA, Small Interfering; C000595779:SRSF1 protein, human; D000068103:Serine-Arginine Splicing Factors
keywords: Immune mediators; JC virus; Neuroimmune interaction; PML; Reactivation; Replication; SRSF1; Stable cells; Transcription