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.
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Acknowledgments
The authors thank the past and present members of the Department of Neuroscience and Center for Neurovirology for sharing their ideas and reagents, particularly Dr. Kamel Khalili. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award numbers R01AI101192 and R21NS081447. This study utilized services offered by core facilities of the Basic Science II Core Facility of the Temple P30 Comprehensive NeuroAIDS Center, Department of Neuroscience (CNAC NIMH Grant Number P30MH092177) at the Lewis Katz School of Medicine at Temple University School. The funding organizations played no role in the design of the study, in the collection, analysis, and interpretation of the data, or in the decision to submit this manuscript for publication. This work was partially presented at the 12th International Symposium on NeuroVirology meeting October 29–November 2, 2013, Washington DC, USA.
Author contributions
Conceived and designed the experiments: IKS. Performed the experiments: RS and FIDS. Analyzed the data: IKS and JG. Contributed reagents/materials/analysis tools: IKS and JG. Wrote the paper: IKS.
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RS and FIDS contributed equally to this work.
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Sariyer, R., De-Simone, F.I., Gordon, J. et al. Immune suppression of JC virus gene expression is mediated by SRSF1. J. Neurovirol. 22, 597–606 (2016). https://doi.org/10.1007/s13365-016-0432-9
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DOI: https://doi.org/10.1007/s13365-016-0432-9