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Title: The roles of DUSPs in respiratory viral infection
Author: Manley, Grace C. A.
ISNI:       0000 0004 6494 1395
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2018
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Exacerbations of airway disease are significant causes of morbidity and mortality. They are often associated with viral infections, most commonly rhinovirus. Rhinoviral infection of airway epithelial cells initiates several signalling pathways, including the MAPK pathways, leading to the production of inflammatory cytokines. It is of extreme importance that these pathways are regulated to prevent excessive inflammation. Dual specificity phosphatases (DUSPs) are known to negatively regulate the MAPKs in bacterial infection of macrophages. I hypothesised that DUSPs would play an important role in regulating the inflammatory response to rhinoviral infection. The response of primary bronchial epithelial cells (PBECs) to rhinoviral infection, stimulation with the synthetic double-stranded RNA poly(I:C), or the inflammatory cytokine IL-1b, was characterised. Stimulation or infection of PBECs led to production of inflammatory cytokines, which was reduced by p38 or JNK inhibitors. Two DUSPs previously found to regulate these pathways, DUSPs 1 and 10, were expressed in PBECs. Interestingly, DUSP1 expression was not regulated in response to viral infection but was increased at the mRNA level by poly(I:C). All stimuli induced phosphorylation of DUSP1. In contrast, DUSP10 expression was found to be decreased rapidly and transiently in response to infection with the minor group virus RV1B, but not by the major group virus RV16, or poly(I:C), or IL-1b. siRNA knock down of DUSP10 did not show a direct role in the regulation of cytokine production in response to rhinovirus or poly(I:C). However, DUSP10 knock down cells consistently produced higher CXCL8 in response to IL-1b stimulation, an important molecule in communication between macrophages and epithelial cells. Rhinovirus replicated well in monocytes, and transfer of supernatants from monocytes to PBECs induced CXCL8 production, which was increased when DUSP10 was knocked down. These data suggest that the MAPK proteins p38 and JNK play important roles in the inflammatory response to rhinovirus. DUSPs 1 and 10 are both expressed in PBECs, and DUSP10 plays an important role in regulating the inflammatory response to IL-1b, and thus, airway inflammation. This study identified DUSP10 as a potential target for future therapeutics aimed at limiting the inflammation caused by rhinoviral infection.
Supervisor: Parker, Lisa ; Sabroe, Ian Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available