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Identification of a ciliary defect associated with pulmonary nontuberculous mycobacterial disease 10.17863/CAM.16360 Fowler, Cedar Over the past several decades, the rate of pulmonary nontuberculous my- cobacterial (PNTM) disease has been increasing. PNTM patients gener- ally consist of lean and tall women presenting with symptoms in the sixth decade of life. They have a de nitive morphophenotype, but no consistent immunological abnormalities despite extensive investigation. I hypothesized that respiratory epithelial dysfunction might play a critical role in PNTM disease predisposition because diseases with defects of mucociliary transport have high rates of PNTM disease that increase with age, suggesting a direct connection between airway epithelial function and PNTM disease. I found that PNTM patients have a distinct respiratory epithelial phenotype ex vivo and decreased nasal nitric oxide levels in vivo. The PNTM ex vivo phenotype consists of an abnormally low resting ciliary beat frequency (CBF) and abnormal CBF response to toll-like receptor (TLR) agonists. The depressed baseline CBF response in PNTM patient cells can be normalized ex vivo by augmenting the nitric oxide-cyclic guanosine monophosphate pathway without appreciable e ect on CBF in healthy controls. In healthy controls, bacterial TLR agonists increase CBF and viral TLR agonists decrease CBF. In PNTM patients these responses are impaired and are not normalized with the normalization of the resting CBF rate. Inhibitor-induced disruption of signalling pathways associated with CBF regulation demonstrated that the majority of the CBF response to TLR agonists involves the PI-3K pathway and PKC. Inhibition of the PI-3K pathway (PI-3K , Akt1, and PDK1) closely mimicked the ex vivo phenotype seen in PNTM patient respiratory epithelia. These data identify a novel aspect of PNTM disease with in vivo and ex vivo correlates that suggest that PNTM infection is associated with abnormal function at both the CBF and TLR response levels. This phenotype is novel, reproducible, and provide a foundation with which to determine the genetic basis of PNTM infection. University of Cambridge 2013-10-08 Thesis Doctoral Doctor of Philosophy (PhD) en_US This work was supported by National Institutes of Health grant 9U54HL096458-06 and by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases. https://www.repository.cam.ac.uk/handle/1810/245062 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/de4aecb3-a00a-4127-8b32-3082257a5c83/download a3d180795b46c0ad5ae8c2f6e804fe9b https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/eeaf348b-50fa-4090-ae0e-55ed668c5416/download 835269bda140c10400fe0606a14c3d21 https://www.rioxx.net/licenses/all-rights-reserved/ Toll-Like Receptors Cilia Nontuberculous Mycobacterium Infections Nitric Oxide Lung Disease Respiratory Mucosa Female Human Ciliary Beat Frequency PI-3K Sildenafil Primary Ciliary Dyskensia Cystic Fibrosis AKT