Enteric fever is major health issue in developing countries and it is becoming progressively untreatable due to increase of antimicrobial resistance. The causative agent, Salmonella enterica, replicates in host phagocytes in various organs and regulates expression of hundreds of genes in response to host signals. PhoPQ is one of the key regulators and essential for virulence in humans and in a mouse typhoid fever model. The sensor kinase PhoQ responds to diverse stimuli (Mg2+ limitation, low pH, cationic antimicrobial peptides, high osmolarity, and, indirectly, to reducing conditions). However, which signals are predominant in vivo remains unclear. To address this issue, we determined the activity of the PhoPQ regulon using a chromosomally encoded fusion of the PhoP-dependent phoNp promoter to gfp-ova and we quantified single-cell fluorescence levels of Salmonella in spleen of infected mice using flow cytometry. The results show extensive heterogeneity in PhoP-activities in the Salmonella population. Comparison of mutants with sensing defects suggests that, in vivo, PhoQ responds to a combination of antimicrobial peptides, acidic pH and low Mg2+, but not to reducing conditions. Negative feedbacks have also only a minor impact. Single-cell analysis of phoNp and asrp promoters suggests differential environmental pH as a major driver of heterogeneous PhoP activities. A combination of immunohistochemistry and proteomics of Salmonella from infected samples was used to validate this hypothesis. Together, our data show how Salmonella uses the PhoPQ system to integrate various host signals in order to tune expression of virulence factors to the diverse tissue microenvironments that this pathogen inhabits.


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