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bioRxiv · 10.64898/2026.01.28.702237

Bloodstream-associated Salmonella Typhimurium and Enteritidis iNTS pathovariants hyper-replicate in human macrophages

Amadeo, F.·Held, M.·Pennington, S. H.·Biagini, G. A.·Hinton, J. C. D.·Cattelan, N.
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Abstract

Invasive non-typhoidal Salmonella (iNTS) are a major cause of bloodstream infections in sub-Saharan Africa, yet the host-pathogen interaction mechanisms remain poorly understood. Here, we developed and optimised a human macrophage infection model based on PMA-differentiated THP-1 cells to investigate infection dynamics of clinically relevant Salmonella Typhimurium and Salmonella Enteritidis strains. We compared intracellular survival and replication of gastroenteritis-associated and bloodstream-associated pathovariants, including S. Typhimurium ST313 Lineage 2, the novel S. Typhimurium ST313 Lineage 3 and the understudied S. Enteritidis Central/Eastern African (CEAC) clades. Our results reveal that the CEAC S. Enteritidis and ST313 S. Typhimurium iNTS pathovariants hyper-replicate within host cells, compared to global epidemic isolates. The cellular model achieved robust pro-inflammatory polarisation of human macrophages, while revealing limitations in modelling macrophage plasticity. Overall, this work defines clear differences in intracellular behaviour of Salmonella pathovariants and establishes a robust experimental framework for future studies on invasive disease pathogenesis and therapeutic interventions that target iNTS bacteria.

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Amadeo, F., Held, M., Pennington, S. H., Biagini, G. A., Hinton, J. C. D., Cattelan, N.. 2026-01-28. Bloodstream-associated Salmonella Typhimurium and Enteritidis iNTS pathovariants hyper-replicate in human macrophages. https://doi.org/10.64898/2026.01.28.702237

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