Exploring serine arginine rich splicing factors and serine arginine protein kinase on rhinovirus infection in airway epithelial cell function

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Studentship strategic priority area:Basic Bioscience Underpinning HeathKeywords:Rhinovirus C, splicing factors, paediatric chronic asthma How respiratory epithelial gene expression is altered in order to optimize viral production for the picornavirus, rhinovirus C is still uncertain. Studies have suggested that viruses can do this by the dysregulation of post-transcriptional RNA processing and export, mRNA stability and mRNA translation on the ribosome. We have recently completed a transcriptomics analysis of nasal epithelial cells obtained from children with pre-asthma infected with rhinovirus A and C. Rhinovirus A and C have different cellular entry mechanisms and unsurprisingly we have found several differences in the gene expression pattern of know host proteins that could explain the differences in the severity of response to these viruses. In addition to the known pathways involved in immune response and host defence we have uncovered potential molecular mechanisms for how these viruses may usurp the epithelial cell's machinery. Namely by altering:. serine/arginine protein kinase 1 (SRPK1) - a regulator of both constitutive and alternative host RNA splicing by regulating intracellular localization of splicing factors and. serine/arginine-rich splicing factors (e.g. SRSF6) - these proteins and their phosphorylation by specific protein kinases, particularly SRPK1, constitute control circuits to regulate both constitutive and alternative pre-mRNA splicing and coordinate splicing with transcription in cells. These proteins can also control mRNA export, stability andtranslation.Surprisingly we have observed a good correlation between expression levels of SRPK1 and some SRSFs including SRSF2, SRSF6, SRSF9 and SRSF11. It is also intriguing that SRPK1 has been reported to phosphorylate some SRSFs including SRSF2 and SRSF6. Although, SRSF protein phosphorylation by SRPK1 directly regulates alternative splicing little is known about the function of SRSF6. Finally SRPK1 inhibitors have antiviral activities against Hepatitis C virus, HIV and Sindbis virus and cytomegalovirus. The significance of these in vivo transcriptomic changes caused by rhinoviral infection of human nasal epithelial cells on SRSFs phosphorylation/activity (host cell RNA splicing) and its consequent on epithelial cell function and host defence and rhino-viral replication is not known.This project aims:1. To determine whether the SRPK1 - SRSF6 axis controls specific host splicing events.2. To understand whether the regulation of the SRPK1 - SRSF6 axis is important to upper airway epithelial function.3. To understand whether the regulation of the SRPK1 - SRSF6 axis is important to how rhinovirus exerts controls over epithelial gene expression to optimise viral production.