Mechanisms of microbiota resilience to infection-induced oxidative stress

• Applicant: Dr. Igor Iatsenko
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Microbial Ecology and Applied Microbiology ; Metabolism, Biochemistry and Genetics of Microorganisms
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 537632283

The resilience to host inflammatory responses induced by an infection is a fundamental property of healthy gut microbiota. Despite importance for the host health, the mechanisms of microbiota resilience remain poorly understood. Recently, we have shown that the resistance of prominent gut commensals to host antimicrobial peptides (AMPs) is an essential resilience mechanism. However, beyond AMPs, other immune effectors can target commensals too. Particularly, reactive oxygen species (ROS) are conserved antimicrobials rapidly induced after infection. This raises the question of how the microbiota remains stable after a ROS burst. Building upon our preliminary results, we hypothesize that gut commensal resistance to ROS is a key property of microbiota entailing resilience during infection-induced oxidative stress. To test this hypothesis, we will use the fruit fly Drosophila melanogaster and its gut commensal Lactiplantibacillus plantarum as a genetically-tractable model. First, in a genetic screen, we will identify and characterize L. plantarum transposon mutants sensitive to ROS. Second, we will generate deletion strains for promising transposon-identified candidates and characterize them regarding general fitness and cross-sensitivity to multiple stressors. Third, a subset of L. plantarum mutants sensitive specifically to ROS in vitro will be tested for the ability to colonize the Drosophila gut under standard lab conditions and after dietary-induced oxidative stress. Next, we will test the persistence of ROS-sensitive L. plantarum in the gut during infection-induced oxidative stress. Finally, we will investigate the contribution of interspecies interactions between gut microbes to the persistence of ROS-sensitive L. plantarum mutants during infection-induced oxidative stress. Overall, in this project, we will identify and characterize molecular mechanisms of the microbiota resistance to ROS; investigate the role of these mechanisms in the microbiota resilience to oxidative stress in vivo; test the role of the community context and cross-protection in the microbiota resilience during infection. The fundamental knowledge gained here will not only advance our understanding of the microbiota resilience mechanisms, but could also help to manipulate individual microbiota members or design microbial communities to make them more resilient to infection-induced perturbations, thus reducing the adverse effect of infection on intestinal homeostasis.

• DFG Programme: Research Grants