Innate immunity and inflammation in cystic fibrosis lung disease

• Main Author: Blohmke, Christoph Johannes
• Language: English
• Published: University of British Columbia 2011
• Online Access: http://hdl.handle.net/2429/34559

Inflammatory lung disease is the major life-limiting factor of cystic fibrosis (CF) and occurs through a self-sustaining cycle of airway obstruction, infection and inflammation. Although there is no consensus regarding the pathways responsible for the excessive inflammation, reducing lung-damaging pro-inflammatory responses are likely to be beneficial for CF patients. Using CF (IB3-1) and non-CF control (C38) respiratory cells, the host-pathogen interaction between the airway epithelium and the common CF pathogens P. aeruginosa and B. cepacia was investigated. Using purified Toll-like receptor (TLR) ligands and different knock-out strains of P. aeruginosa, TLR5 was identified as the receptor mediating much of the increased inflammatory response to CF pathogens. To validate TLR5 as an anti-inflammatory target, the disease modifying effects of the functionally relevant TLR5 c.1174C>T single nucleotide polymorphism (rs5744168) was analysed in approximately 80% of Canada’s CF population. rs5744168 encodes a premature stop codon and the T allele is associated with 45.5 – 76.3% reduction in flagellin responsiveness. CF patients carrying rs5744168 (CT or TT) had a significantly higher body mass index than CF patients homozygous for the common allele (CC) (p=0.044); however, similar improvements in lung function associated with the T allele were not statistically significant. Since TLR5 mediates much of the excessive inflammation to P. aeruginosa, it is of interest to understand the mechanisms underlying this dysregulated immune response. By combining gene expression arrays with network analyses and biochemical assays, ER stress was identified as a potential mechanism dysregulating p38 MAP kinase activity and leading to potentiated immune responses. Together, this thesis provides data underscoring the importance of TLR5-mediated excessive pro-inflammatory immune response by CF airway cells to P. aeruginosa. The association of the TLR5392STOP SNP with higher BMI in adult CF patients indicates an important role for TLR5 in CF disease severity. Finally, ER stress may potentiate the immune response to flagellin by signalling through p38 MAP kinase, supporting an emerging paradigm in which the imbalance of protein homeostasis can lead to altered signalling events. Strategies to inhibit either TLR5 signalling, ER stress signalling or to improve the cellular protein homeostasis may prove useful in treating life limiting inflammation in CF. === Medicine, Faculty of === Medicine, Department of === Experimental Medicine, Division of === Graduate