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Title: Role of TRAF6 and TAK1 in rhinovirus induced chemokine gene expression and airway neutrophilia in vitro and in vivo
Author: Haas, Jennifer Jane
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Virus induced asthma exacerbations are a significant cause of morbidity and mortality and the means by wh ich rhinoviruses exacerbate asthma is poorly understood. Rhinovirus infection, produces an immediate innate anti-vira l response dominated by type I interferon and type Ill interferon and an inflammatory response including airway neutrophilia . Interferon induction is conside red beneficial and is defect ive in asthmat ics. Meanwhile, neutrophil inflammation correlates w ith symptoms, suggesting neutrophils contribute to pathology. Current data suggests inflammat ion in asthma is mediated at least in part by NF-KB activat ion, a novel therapeutic target for asthma exacerbations. A caveat to this idea is that NF-KB signa lling may a lso be required for interferon product ion. Therefore, establishing wh ich signa lling pathways lead to inflammation yet are dispensa ble for interferon induction may uncover novel therapeutic targets for asthma exace rbations. Here we investigated the role of TAKl and TRAF6,during rhinovirus infection both in vitro and in vivo. Using small interfering siRNA, over expression studies and a TAKl inhibitor (LL-Z-1640-2) we found that TAKl and TRAF6 were required for neutroph il chemok ine mRNA express ion but not interferon . TAKl's role during RV- B infection in vivo was investigated using a mouse model of rhinovirus infection and administration of LL-Z-1640-2, wh ich inhibited RV induced airway neutroph ilia while simultaneous ly augmenting RV induced pro-inflammatory cytokines, prompting us to question its specificity and efficacy in vivo. We a lso investigated TAKl and TRAF6 express ion in HBECs cultured ex vivo from asthmat ic patient's bronchia l brushings and found no significant increase in TAKl or TRAF6 expression, and no correlatat ion w ith various clinica l outcomes. In summa ry, this is the first study investigating the role of TAKl and TRAF6 in RV induced responses in vitro and in vivo and these findings indicate that targeting TAK1/TRAF6 to treat virus induced asthma exace rbations may be an effective approach by suppressing pro-inflammatory cytokine/neutrophilic inflammatiion, wh ille preserving interferon responses.
Supervisor: Edwards, Michael ; Johnston, Sebastian Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available