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Abstract

Introduction

HRV infections cause asthma exacerbations, while HRV-induced wheezing in pre-school children is associated with asthma development in later life. Molecular mechanisms underlying this pathophysiology remain elusive, while HRV-C is increasingly associated with disease severity. Transcriptomic analysis of human respiratory (nasal) epithelia from an in vivo HRV-C infection model revealed changes in expression of cellular Serine/Arginine Protein Kinase 1 (SRPK1) and its substrates, the Serine/Arginine Splicing Factors (SRSFs) suggesting that HRV infection targets pre-mRNA splicing and/or its regulating factors.

Hypothesis

1) HRV splicing modulation results in host transcriptome changes, leading to impaired anti-viral responses and/or immunoregulation; 2) HRV-induced changes to SR proteins result in enhanced HRV-translation and replication.

Methods

HRV-A RNA was synthesised by in-vitro transcription from pRV16.11. HRV replication was measured by RT-qPCR and titration in HeLa cells. Protein expression was monitored by western blotting and confocal microscopy. SPRIN340 was used as a specific SRPK1 inhibitor. Alternatively, SRPK1 was depleted via siRNA interference.

Results

1) SRPK1, SRSF1-6 and SRSF9 are expressed in both A549 and HeLa cells; levels were greater in the latter. 2) SRPIN340 and siSRPK1 treatments decrease the levels of SRPK1 leading to decreased expression of SRSFs in HeLa and A549 cells. 3) HRV16 infection decreased SRPK1, SRSF1-6 and SRSF9 expression in HeLa and A549 cells.

Conclusion

Our initial data suggest that HRV-infection specifically alters molecules involved in pre-mRNA splicing, providing us with insights into the molecular mechanisms underlying the distinct pathology of HRV infection, as well as the aetiology of HRV-associated asthma.

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/content/journal/acmi/10.1099/acmi.ac2019.po0440
2019-04-08
2019-10-14
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http://instance.metastore.ingenta.com/content/journal/acmi/10.1099/acmi.ac2019.po0440
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