Abstract
Important roles of microRNAs (miRNAs) in regulating the host response during viral infection have begun to be defined. However, little is known about the functional roles of miRNAs within an in vivo acute viral encephalitis model. We therefore identified global changes in miRNA expression during acute herpes simplex virus type 1 (HSV-1) encephalitis (HSVE) in mice. We found that many of the highly upregulated miRNAs (miR-155, miR-146a and miR-15b) detected in HSV-1 infected brain tissue are known regulators of inflammation and innate immunity. We also observed upregulation of 7 members belonging to the related group of miRNAs, the miR-200 family and miR-182 cluster (miR-200/182). Using in situ hybridization, we found that these miRNAs co-localized to regions of the brain with severe HSVE-related pathology and were upregulated in various cell types including neurons. Induction was apparent but not limited to cells in which HSV-1 was detected by immunohistochemistry, suggesting possible roles of these miRNAs in the host response to viral-induced tissue damage. Bioinformatic prediction combined with gene expression profiling revealed that the induced miR-200/182 members could regulate the biosynthesis of heparan sulfate proteoglycans. Using luciferase assays, we found that miR-96, miR-141, miR-183 and miR-200c all potentially targeted the syndecan-2 gene (Sdc2), which codes for a cell surface heparan sulfate proteoglycan involved in HSV-1 cellular attachment and entry.
Highlights
Herpes simplex virus type 1 (HSV-1) typically infects the host at the epithelial surface through mucosal secretions, becomes latent and resides within the trigeminal ganglia
We examined the changes in cellular miRNA expression in acute HSVE mouse brain tissues and using next generation sequencing (NGS), a list of miRNAs that were deregulated during HSVE was identified
Using the target prediction software TargetScan in conjunction with gene expression profiling, we found that miR-200/182 may modulate the biosynthesis of heparan sulfate proteoglycans (HSPGs)
Summary
Herpes simplex virus type 1 (HSV-1) typically infects the host at the epithelial surface through mucosal secretions, becomes latent and resides within the trigeminal ganglia. The virus reactivates and causes recurrent lesions at primary sites of infection. Upregulation of miR-200/182 during HSVE virus reactivate and disseminate within the brain tissue causing herpes simplex encephalitis (HSVE) [1]. HSVE is the most commonly recognized cause of acute encephalitis with an incidence rate of 2–4 individuals/million annually [2]. Mortality rates of HSVE can reach !70% and even after successful treatment the severe neurological damage that occurs during disease can result in lifelong disability [3]. A vast array of data has been collected over the years describing the gene networks that are disrupted during HSVE [4,5,6], the upstream regulatory pathways that control the expression of these genes within an in vivo environment remain poorly understood
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