Decoding Persistent Salmonella Infections: High Throughput Exploration of Molecular Decision Points

Bacterial pathogens exhibit resistance to antibiotic treatments through either antimicrobial resistance mechanisms or the adoption of bet-hedging strategies, where a slow-growing subpopulation becomes tolerant to antibiotics (persisters). Such treatment-resistant pathogens not only contribute to the spread of antibiotic resistance but are also linked to chronic and recurring infections. While extensive research is conducted to decipher the mechanisms of antibiotic resistance, it is largely unknow how the existence of persister subpopulations is triggered and sustained during infections, hindering the development of efficient treatment strategies. To address this research gap, we have designed a high-throughput approach to uncover key molecular decisions for sustaining or aborting a persistent state during Salmonella infections within macrophages. Our approach involves the simultaneous targeting of the bacterium and the macrophage using a combination of antibiotics and immunomodulatory drugs to identify conditions that modify Salmonella's intracellular survival. Subsequent in-depth exploration of the most promising conditions will unveil the genetic landscape of bacterial and host pathways facilitating intracellular pathogen survival and or exit from the persistence state. In the long term, we aim to investigate how pathogen- or host cell-specific our findings are, which will hint towards the need for broad-spectrum or targeted therapies.