African Typhimurium Lineages Adaptation Study

The ATLAS project tackles a critical paradox in bacterial evolution: the rise of pan-susceptible S. Typhimurium ST313 Lineage 3 (L3), which is displacing multidrug-resistant Lineage 2 (L2) across sub-Saharan Africa, a region where invasive non-typhoidal Salmonella causes around 77,500 deaths annually. This phenomenon challenges the prevailing view that antibiotic resistance is the main driver of pathogen success. Building on the host laboratory's discovery of L3 and preliminary evidence of its hyper-replication in macrophages, ATLAS seeks to uncover why L3 thrives despite lacking antimicrobial resistance. ATLAS employs a uniquely integrative strategy combining phenogenomics, functional genomics, and multi-omics analyses. We will compare L2 and L3 isolates using parallel workflows: phenotypic assays and pangenome analysis (WP1), coupled with dual RNA-seq, Tn-seq during macrophage infection, and integration with genome-scale metabolic models (WP2). These datasets will converge in WP3 through GWAS and a comprehensive comparative network analysis to reveal the mechanisms driving lineage replacement. This integrated approach is essential to capture the interplay of virulence, metabolism, and immune evasion, factors invisible to single-method studies. By focusing on circulating L3 strains and applying simultaneous multi-omics integration, ATLAS moves beyond prior studies limited to early isolates and sequential analyses. Leveraging the host lab's optimized protocols, Tn-seq libraries, and transcriptomic resources, the project will generate transformative insights: L3-specific virulence mechanisms and metabolic adaptations enabling systemic infection will be mapped, creating at the same time an open-access atlas of ST313 evolution. This resource will shift the field from descriptive observation to predictive frameworks, providing the basis to determine whether metabolic efficiency and immune evasion can outweigh antibiotic resistance in bacterial success.