Using genomics to understand the role of cystic fibrosis pathogens in pulmonary exacerbations. (360G-Wellcome-110224_Z_15_Z)

CF is an inherited, life-limiting, multi-system disorder, for which acute deteriorations in lung function termed 'acute pulmonary exacerbations' (APEs) are the single most important cause of morbidity and mortality. Despite this, little is understood about the pathophysiological processes that trigger APEs, although they are thought to be driven by respiratory infections. However, there is no substantive evidence to date that the presence or load of individual species is driving this process. Th is may reflect the complex underlying microbial diversity found in the CF lung at both the inter and intra species level. Therefore, directly sampling of this diversity using high-throughput sequencing will enable major advances in our understanding of APEs. This project involves two approaches which may lead to the discovery of the microbial factors which drive the progression of APE's:(a)Targeted enrichment technology to enable genomic sequencing of multiple CF pathogens concurrently. This w ill enable a greater understanding of the evolutionary dynamics of CF pathogens in the context of APEs. (b)Temporal clonal analysis of Pseudomonas aeruginosa isolates which have been phenotyped for characteristics related to bacterial virulence. By applying a genome wide association analysis we will gain a greater understanding of the relationship between genetic diversity and phenotype.