Investigating the inter-relationship of SRPK1 and HRV infection

Human rhinoviruses (HRV) are a leading cause of the common cold, but can often lead to respiratory complications in immunocompromised groups, evidently in a species-associated manner. There has been a growing interest in what underlies the variability in the severity of induced disease between HRV A, B and C strains. Koo et al. investigated this at the transcriptomic level in respiratory epithelial cells harvested from children, hospitalised with acute wheezing episodes. (https://doi.org/10/4049/j.immunol.1800178). Interestingly, this study revealed significant alterations in the expression of key host cell splicing factors between some HRV-infected children and uninfected controls, mainly the Serine/Arginine Protein Kinase 1 (SRPK1) and several Serine/Arginine rich Splicing Factors (SRSFs). As these splicing factors regulate host splicing and translation, we hypothesise that HRV infection regulates the kinase SRPK1 and its substrates SRSFs to either dysregulate the splicing of host mRNAs performing antiviral functions and/or to alter the translation of viral proteins. We initiated this investigation by exploring HRV-A infections in-vitro using the strain HRV16. Here, we show that the pharmacological inhibition as well as the overexpression of SRPK1 has a direct and opposing effect on HRV16 infection in primary bronchial epithelial cells. In the same system, HRV16 infection led to significant downregulation at the gene, protein and phosphorylation levels of SRPK1 as well as of SRSF1, SRSF3 and SRSF6. Transcriptomic and alternative splicing (AS) bioinformatic analysis was performed using a physiologically relevant primary bronchial epithelial 3D model. This revealed the significantly altered AS of 1228 host genes during infection, with subsequent pathway analysis enriching the vast majority of these genes in cilia development and function networks. The impact of this effect has been demonstrated here, with HRV16 infection leading to significantly decreased cilia length and total numbers in our primary bronchial epithelial 3D model. Overall, this investigation has unravelled novel networks implemented during HRV infection and provided insights into the association of recurrent HRV infections at an early age with respiratory complications during development.