Ecological and evolutionary strain-level dynamics of key pathogens in the cystic fibrosis lung microbiome.
About the Project
People with cystic fibrosis (pwCF) harbour chronic lung infections caused by a variety of bacterial pathogens. In the CF airway, mucus accumulates in the lungs potentiating the development of a taxonomically diverse lung microbiome. Variation in these microbiomes cause periodic pulmonary exacerbations (defined as worsening pulmonary symptoms including cough, increased sputum production, increased breathlessness) needing hospitalization and treatment with antibiotics.
CF pathogens are genetically diverse and many different strains of key pathogens – such as Pseudomonas aeruginosa – can infect pwCF. These organisms often only share a small proportion of “core genes” (genes found in every strain of a species) whereas “accessory genes” contribute to much of the diversity, pathogenicity, and antibiotic resistance of a species. How variation in the accessory genomes of pathogens affects severity of disease, including frequency of exacerbations, is poorly understood.
This PhD project is funded as part of a large, multi-centre CF Trust Innovation Hub whose objective is to understand the mechanisms underlying pulmonary exacerbation. In this project, the student will ask how different strains of key CF pathogens change over the course of exacerbation, and how the accessory gene content of these strains contribute to exacerbation severity. In particular, the student will combine high-throughput, classic microbiological techniques with next generation DNA sequencing technologies to identify ecological and evolutionary strain-level community dynamics over the course of exacerbation in pwCF. The project includes the following objectives:
1. Use culture-enrichment and metagenomic sequencing to reconstruct the ecological and evolutionary strain-level community dynamics of each pwCF. Clinical samples will be collected from pwCF longitudinally from individuals experiencing pulmonary exacerbation and will be cultured on an array of agars. Each unique strain will be isolated to form pwCF-specific strain biobanks. Culture-enriched metagenomics will be performed to identify the strains present within each pwCF and how these lineages change in response to exacerbation.
2. Quantify how these strain-level dynamics change over the course of exacerbation using the pwCF strain biobank. High throughput phenomic screens (e.g., for antimicrobial resistance, secondary metabolite production, swimming, swarming etc.) will be used to quantify evolutionary changes that occur over the course of the exacerbation. Phenotypic changes will be linked to genotype by correlating the output of the phenomic screens with genetic differences observed in the sequencing data.
3. Identify accessory genes which contribute to intra-genus pathogen inhibition. Previous work on CF pathogens has shown that the first strain to colonize a person with CF often colonizes them long-term. This competition often leads to dominance of a single strain in the pathogenic niche; that is to say that strains of CF pathogens suppress other intra-genus strains in the lung environment. Here, the student will identify the accessory genes within pathogenic strains which are responsible for intra-genus pathogen-pathogen competition.
The outcome of this project is to understand the dynamics of CF pathogens, how exacerbation and clinical treatment (e.g. antibiotic usage) affects these dynamics, and how the accessory genome affects disease severity.
In this project, the student will learn a unique combination of methodologies which will be widely transferable including bioinformatics (e.g., meta/genomic sequencing, pangenomics), microbiology (e.g., culture enrichment), and high-throughput phenomic assays.
Eligibility
Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline.
How to Apply
For information
on how to apply for this project, please visit the Faculty of Biology, Medicine
and Health Doctoral Academy website
(https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries
may be made directly to the primary supervisor.
Equality, Diversity & Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/
Funding Notes
This is a Faculty funded Doctoral Academy studentship, 3.5 years at UKRI level home fees/stipend and RTSG
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