Project B04

Systems biology approach to identify key molecular decision points for intracellular persistence during infection

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Dr. Ana Rita Gontão Brochado

 

Bacterial pathogens escape antibiotic treatment either via antimicrobial resistance mechanisms or by adopting bet-hedging strategies in which a slow growing bacterial subpopulation becomes tolerant to antibiotics (persisters). Bacterial persistence is tightly associated with chronic and recurring infections of a wide range of pathogens, including Salmonella enterica serovar Typhimurium, Chlamydia trachomatis, enteropathogenic Yersiniae, and Staphylococcus aureus. Persistence also contributes to the spread of antibiotic resistance. How bacterial persistence is triggered and sustained during infection is vastly unknown, impairing the design of efficient treatment strategies. This project deploys an innovative approach to uncover key molecular decisions for sustaining or aborting a persistent state during infection using the well-established model system of Salmonella infection of macrophages. We will undertake a chemical perturbation approach, simultaneously targeting the bacterium and the macrophage, to find conditions that alter the intracellular survival of Salmonella persisters. Further investigation of persister survival altering conditions will reveal the bacterial genetic landscape that enables intracellular persistence sustainability and key host pathways (decision points) that can be modulated by bacterial factors in order to bring bacteria out of the persistence state. In the long term, we aim to investigate if our findings are pathogen- or host cell-specific, which will determine the need for broad-spectrum or targeted therapies. Our methods can be easily adapted to directly investigate if the key pathways that regulate Salmonella persistence that we will uncover will also influence persistence by other pathogens, such as C. trachomatis or Yersinia pseudotuberculosis.