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 down-regulation 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.

Pur-Alpha Induces JCV Gene Expression and Viral Replication by Suppressing SRSF1 in Glial Cells

“…SRSF1 is an important host gene controlling JC virus gene expression in glial cells [ 19 – 21 , 32 ]. We have recently showed that SRSF1 expression is regulated by immune signaling, and can be induced by soluble immune mediators (cytokines and chemokines) leading to transcriptional suppression of JC virus [ 33 ]. More importantly, SRSF1 induction is required for the suppression of JCV gene expression and viral replication mediated by neuroimmune conditioning.…”

Alcohol-Mediated Missplicing of Mcl-1 Pre-mRNA is Involved in Neurotoxicity

“…The luciferase reporter plasmid pLuc-SRSF1 was made by cloning the −1000 to +49 promoter region of SRSF1 gene into the pGL3 vector at the BamH1 site and was described previously (Craigie et al, 2015; Sariyer et al, 2016). Human serine and arginine rich splicing factor 1 (SRSF1, NCBI Reference Sequence: NM_006924.4) was cloned into the eukaryotic expression vector pcDNA ™ 6/myc-His at Hind-III and Xho-I restriction enzyme sites and labeled as pcDNA ™ 6/myc-His-SRSF1.…”

Adaptive homeostasis and the p53 isoform network

“…SRSF1 facilitates the production of type I IFNs recognized by the cytoplasmic pattern recognition receptor, RIG1, in psoriatic lesions (Xue et al , 2015 ). SRSF1‐mediated production of type I IFNs also prevents the development of systemic lupus erythematosus (SLE) by restraining T‐cell activation (Katsuyama et al , 2019 ) and is required for neuro‐immune suppression of the human neurotropic JC virus (JCV) (Sariyer et al , 2016 ). Human aortic smooth muscle cells (HASMCs) expressing SRSF1 showed high levels of Δ133p53α isoform and SRSF1‐deficient mice had lower levels of Δ157p53 (orthologue of Δ133p53) compared to controls.…”