Using population genomics to recognise and prevent the emergence and establishment of Klebsiella pneumoniae high-risk lineages

This project will focus on comparative population genomics of three longitudinal collections of K. pneumoniae spanning 12-20 years from three diverse settings; the UK, Argentina and Malawi.

This project will focus on comparative population genomics of three longitudinal collections of K. pneumoniae spanning 12-20 years from three diverse settings; the UK, Argentina and Malawi.

Current data on K. pneumoniae is almost exclusively based on short-term studies of specific wards/hospitals, often in highly different settings. This makes the analysis of long-term signals impossible, as this would require the comparison of highly confounded data, e.g. different years represented by isolates from different countries, making it impossible to distinguish between the influence of time of isolation from the country of isolation.

The comparison of three highly different settings reduces this confounder, as the patient catchment group remains similar over time. To confidently recognise globally applicable signals that are universally valid, this project will compare what triggers lineage expansion in the three different settings with each other. The observed temporal changes in the population in the relevant settings can then be compared with each other, to identify shared rules for what makes a K. pneumoniae lineage successful over others when all share similar AMR determinants.

Understanding what leads to the emergence of new high-risk lineages is essential to form an early-warning system for the emergence of high-risk clones, and focus efforts of infection control on these, especially when resources are limited.

Where does the project lie on the Translational Pathway?

T1 (Basic Research) – T2 (Human/Clinical Research)

Expected Outputs

The project will produce high quality REF returnable 3*/4* publications and will provide the evidence base for large scale research council funding in a global priority area. Previous and current PhD students from EH have all published one or several high-quality first-author papers, including Molecular Microbiology, PLoS Pathogens and Nucleic Acids Research, and have all moved to postdoctoral positions or are working as programmer in industry. Recent work from EH and NAF on multidrug-resistant bacterial population dynamics has resulted in high-impact publications in Genome Biology, Nature Communications and Lancet Infectious Diseases. The project will have the unique opportunity to access three longitudinal collections spanning 12-20 years of the UK, Argentina, and Malawi, which is an unprecedented dataset to study long-term dynamics of K. pneumoniae and will give us unique, high-impact insights into the dynamics during its exceptionally fast rise as multidrug-resistant pathogen. The student will furthermore be embedded in the larger collaborative network on K. pneumoniae around EH, CJ and NAF, which includes Prof. Corander (associate faculty at Wellcome Sanger Institute, faculty at University of Oslo and University of Helsinki), Dr. Cornick (group leader at UoL/MLW) and Dr. Corso (head of the antimicrobial reference center for Argentina, ANLIS). This is a key strategic area for LSTM as evidenced by the recent appointment of EH who was recruited from the prestigious Wellcome Sanger Institute.

Training Opportunities

Training will be provided in bioinformatics (molecular evolution, comparative genomics, population genomics), statistics, and epidemiology. The student will furthermore work with collaborators at the Wellcome Sanger Institute, Lancaster University, and the MLW, and be embedded in the already closely collaborating network between the supervisory team and further collaborators.

Skills Required

The student should be interested in bioinformatics, and with an interest in genomics and infectious disease epidemiology.

Key Publications associated with this project

Cornick et al. 2020 bioRXiv 10.1101/2020.08.06.236117 Genomic investigation of a suspected multi-drug resistant Klebsiella pneumoniae outbreak in a neonatal care unit in sub-Saharan Africa

Ellington, Heinz et al. 2019 Genome Biology Contrasting patterns of longitudinal population dynamics and antimicrobial resistance mechanisms in two priority bacterial pathogens over 7 years in a single center.

Musicha et al. 2017 Lancet Infectious Disease Trends in antimicrobial resistance in bloodstream infection isolates at a large urban hospital in Malawi (1998-2016): a surveillance study.

Miller et al. 2017 PLoS Computational Biology sourceR: Classification and source attribution of infectious agents among heterogeneous populations.

Musicha et al. 2019 Journal of Antimicrobial Chemotherapy Genomic analysis of Klebsiella pneumoniae isolates from Malawi reveals acquisition of multiple ESBL determinants across diverse lineages.

Deadline: Thursday 11th February 2021; 12:00 noon GMT

Further details on the MRC/DTP and CASE programmes and application guidance and process can be found here