Host-Targeted Perturbations for Eradication of Recalcitrant Salmonella Infections

Salmonella is defined as a WHO-priority pathogen due to rising antimicrobial resistance. During antibiotic treatment, reservoirs of invasive non-typhoidal Salmonella capable of seeding infection relapse (called persisters) survive within macrophages. Eradication of persisters is challenging, necessitating sustained inflammation that can exacerbate Salmonella infection-associated pathology. Therapeutic technologies precisely modulating expression of individual genes in innate immune cells raise the possibility of controllably tuning macrophage phenotype for safe eradication of persisters. It remains unclear, however, how exactly this can be achieved. Here, we aim to identify host-directed perturbations enabling Salmonella persister eradication in the clinic. Focussing on host transcription factors and chromatin regulators, we will first identify and characterise candidate loss-of-function and gain-of- function perturbations redirecting persister-infected macrophage transcriptional networks to favour persister clearance. We will then use causal deep learning approaches and clinical data to determine which candidate perturbations are most likely to have therapeutic impact in patients undergoing antibiotic treatment for non-typhoidal Salmonella disease. In later years, we will extend our research to other bacterial infections where macrophage-resident persisters are similarly associated with infection relapse (Salmonella Typhi, Mycobacterium tuberculosis, Staphylococcus aureus). Collectively, we anticipate that our research will pave the way for development of next-generation antibacterial immunotherapies to eradicate recalcitrant infections.