Dissecting the RNA-centric landscape of microbiota-pathogen interactions in the gut

• Applicant: Professor Alexander Westermann, Ph.D.
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Metabolism, Biochemistry and Genetics of Microorganisms
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545774017

The microbiota plays a critical role in maintaining human and animal health through providing ‘colonisation resistance’ against invading bacterial pathogens. However, diverse pathogens belonging to the Proteobacteria (such as pathogenic E. coli) can exploit the natural function of anaerobic symbionts (such as Bacteroides thetaiotaomicron) to establish an infectious niche or reservoir for dissemination. This is achieved through the scavenging and sensing of dietary metabolites liberated by Bacteroides during digestion as regulatory effectors that stimulate the expression of virulence or fitness factors. This molecular crosstalk between commensal and pathogenic species underlies infection but our understanding of these interactions in vivo is in its infancy. Determining how B. thetaiotaomicron and pathogenic E. coli regulate gene expression globally within the gut niche is key to understanding their function during interactions in vivo. Bacterial small noncoding RNAs (sRNAs) influence metabolic, stress-response and virulence gene expression via diverse mechanisms. Discovery and characterisation of sRNAs in pathogens is well established, however the roles these RNAs play in vivo are poorly understood. Even more so, our understanding of post-transcriptional regulation in commensal microbiota species such as B. thetaiotaomicron is extremely limited. In this project, we will study the impact of the host¬-environment on bacterial sRNA-mediated gene expression control. Specifically, we will test our overarching hypothesis that specific regulatory RNA mechanisms, triggered in response to the host environment, will play key roles in the interaction between commensal bacteria and pathogens within the gut. We will combine innovative cross-species transcriptomics and CRIPSR-based functional genomic approaches with relevant in vivo models to identify fitness-promoting sRNAs in B. thetaiotaomicron and uropathogenic E. coli (UPEC) or C. rodentium, used to model gut colonisation or zoonotic enteropathogenesis respectively. The importance of those sRNAs and their role in host colonisation will be determined using classical genetics, biochemistry, and functional assays. Our work will reveal new insights into the underlying molecular mechanisms of colonisation resistance and infection and has the potential to reveal new therapeutic avenues.

• DFG Programme: Research Grants
• International Connection: United Kingdom
• Cooperation Partner: Professor James Connolly, Ph.D.