Biochemistry and Pharmacology - Theses
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ItemInvestigating features and interactions of the childhood respiratory microbiome( 2022)The human microbiome is closely linked with the health of an individual and is implicated in numerous complex diseases including diabetes, inflammatory bowel disease, cancer, cystic fibrosis (CF), and asthma. There is growing evidence to suggest the respiratory microbiome influences risk and trajectory of respiratory disease from an early age. Hence, unravelling the biology of the childhood respiratory microbiome is critical to gain a comprehensive understanding of respiratory disease, and requires characterisation of both the aggregate community and individual community members. This thesis strengthens our understanding of the childhood respiratory microbiome through i) investigation of specific community members, Haemophilus influenzae and Haemophilus parainfluenzae, in the context of CF, and ii) exploration of upper respiratory tract (URT) microbiome development during the first year of life with a particular focus on microbe-microbe interactions. While morbidity and mortality of CF principally result from repeated respiratory infections by Pseudomonas aeruginosa, there is emerging evidence that respiratory tract colonisation by Haemophilus species during childhood induces early disease progression. I describe the detection, antimicrobial resistance (AMR), and genome sequencing of H. influenzae and H. parainfluenzae isolated from airway samples of children enrolled in the AREST CF program. This work revealed H. influenzae and H. parainfluenzae carriage rates and strain persistence among participants. Haemophilus isolates were genetically diverse and commonly resistant to antimicrobials with several putative novel resistance determinants identified. Finally, genomic data identified transmission of Haemophilus strains between participants. The association between the respiratory microbiome and respiratory disease has been established in several cohort studies. However, no work has been undertaken to compare preservation of respiratory microbiome dynamics or to reconcile differences between cohort studies. This thesis explores 16S rRNA gene survey data from four longitudinal childhood cohorts, with a focus on microbe-microbe interactions. The URT microbiome composition dynamics during the first year of life are shown to be well preserved across cohorts, and the aggregate data set is leveraged to reveal associations between specific community members and symptoms of acute respiratory illness. A foundation for microbe-microbe interactions during the first year of life is established, which facilitated discovery of two communities that dominate the URT microbiome. For both areas of focus presented in this thesis I additionally developed two novel software tools to support and enhance analysis: hicap, a tool for robust inference of H. influenzae serotype and cap locus structure from WGS data, and FastSpar, a tool for rapid and scalable correlation estimation from compositional data. Collectively, this thesis contributes to our understanding of the childhood URT microbiome in the context of CF and normal development. The results in this thesis provide the first insights into the population dynamics and genomic AMR determinants of H. influenzae and H. parainfluenzae strains in a paediatric CF cohort. The presented findings further recapitulate the most complete overview of URT microbiome development during the first year of life and provide the first foundation for microbe-microbe interaction dynamics. The tools developed and the analyses performed in this thesis provide an important framework for future studies to investigate features and interactions of the respiratory microbiome.