Patho-adaptive Mutations in Helicobacter pylori

• Applicant: Professor Dr. Steffen Backert
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; General Genetics and Functional Genome Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 533816968

A hallmark of the human stomach bacterial pathogen Helicobacter pylori is extensive gene variability between different strains, with a high level of genetic homoplasy, i.e. identical sequence variations in otherwise diverse allelic variants of a gene. The excessive homoplasy has been primarily attributed to frequent intra-genic homologous recombination in this naturally-competent bacterial species. Recent work with our collaborators, however, has demonstrated that convergent gene evolution via repeated mutation is also a key player for generating homoplasy in H. pylori genes. Convergent mutations at specific amino acid positions (i.e. structural hotspot mutations) represent adaptive changes in response to selection pressures, as shown in our recent collaborative work [e.g. for flagellin versus CagL in immune recognition by TLR5 (Pachathundikandi et al. Nature Communications 2019, vol.10:5717 and disease-associated SNPs in protease HtrA (Sharafutdinov et al. Cell Host & Microbe, revised paper submitted)]. We therefore hypothesize that mutational convergence significantly contributes to the adaptation of H. pylori as a pathogen. We propose a novel approach to distinguish convergent mutations from intra-genic homologous recombination through an array of microevolutionary tests and in silico simulation of DNA mutations. We will analyze more than 1,400 newly acquired genome sequences of H. pylori strains of diverse geographic and ethnic origin that were obtained from asymptomatic individuals and from patients with various disease manifestations. Genom-wide association studies (GWAS), transcriptional profiling (RNA-Seq) and functional assays will be performed to validate any adaptive nature of convergent mutations in genes encoding serine protease HtrA, outer membrane adhesins, secretion systems and other virulence factors, as a proof of principle study. The proposed study aims to provide new insights on the dual action of recombination and mutation during positive selection. These studies set the stage for future functional studies of H. pylori candidate genes and potentially adaptive mutations therein, expanding our understanding of the pathogenesis of this critically important pathogen. Besides, the analytical approach that we will develop in this proposal would be pivotal for the analysis of patho-adaptive evolution in other, similarly fast-evolving bacteria, such as Neisseria, Streptococcus etc. that also exhibit excessive genetic homoplasy.

• DFG Programme: Research Grants