Evaluating the genetic basis and evolution of virulence and antimicrobial drug resistance in Helicobacter pylori in a populational model

About the Project

Project background

Characterization of the genetic variation of bacterial species and the evolutionary mechanisms leading to that variation is crucial for understanding bacterial adaptation to their host environments, as well as the evolution of phenotypes such as virulence and antimicrobial drug resistance (AMR). Helicobacter pylori infection is the world’s most common infection worldwide and causes peptic ulcer and gastric cancer - the second leading cause of cancer death. Despite its ubiquity, susceptibility to H. pylori-associated disease varies across hosts and populations. We have been studying the genetic variation of H. pylori in the African nation of Cabo Verde, a unique setting where historical colonization has resulted in a diverse set of European and African H. pylori lineages. We have assembled a dataset of approximately 500 isolates with complete genome sequences. Preliminary analyses show substantial genetic diversity, with between- and within-host differences in virulence and AMR phenotypes. Additionally, there is preliminary evidence of association between these phenotypes and bacterial ancestry. Notably, known genetic determinants of virulence and AMR do not fully account for the observed patterns.

Aim and objectives

Building on these findings, this project aims to further explore the genetic basis and evolutionary dynamics of virulence and AMR, through integrated genomic, computational, and experimental approaches.

The objectives are:

1. To employ genome-wide association analyses (GWAS)¹ and machine learning² to prioritise genes in virulence and AMR
2. To characterise novel molecular mechanisms of AMR by conducting targeted molecular and cellular studies of candidate genes.
3. To investigate evolutionary processes shaping these trains by analysing the genetic variation of validated genes and evaluate the roles of neutral evolution versus natural selection in the evolution of virulence and AMR in this pathogen³.

This research will advance our understanding of how genetic diversity influences pathogenicity and drug resistance in H. pylori, providing insights into bacterial adaptation and informing health-policy strategies for managing infection and AMR.

Training opportunities

The project provides an opportunity to integrate laboratory experiments with computational analyses. The laboratory component includes microbial techniques (bacterial isolation and culture, tests for antimicrobial drug susceptibility), molecular genetics (e.g. DNA extraction, DNA library construction, PCR; mutant construct generation), and Next-Generation Sequencing using paired-end sequencing. The computational component includes genomics (genome assembly and alignment), evolutionary (testing for selection and applying selection models) and statistical (genetic association, machine learning) analyses.

Enquiries

Project Enquiries to sdsb1@leicester.ac.uk

To apply please refer to

https://le.ac.uk/study/research-degrees/research-subjects/respiratory-sciences

References

[1] 10.1038/nrg.2016.132
[2] 10.1371/journal.pcbi.1010018
[3]10.1371/journal.pgen.1011317