Salmonella single-cell dynamics in complex tissues

During infections, host-pathogen interactions occur in complex, dynamically changing host tissues. Our work in a mouse Salmonella infection model shows that pathogen subsets reside in diverse host microenvironments, where they have differential access to host nutrients and disparate exposures to nitric oxide, reactive oxygen species, and drugs. FACSorting and proteome analysis of Salmonella subsets reveal distinct local adaptations involving just a few, or up to hundreds of proteins. During treatment with antibiotics, the various Salmonella subsets differ in their survival with both synergistic and antagonistic interactions between immune effectors and antibiotics. These results show that this salmonellosis consists of strikingly heterogeneous and dynamic Salmonella-host encounters involving diverse tissue regions, cell types, and molecular mechanisms. Overall disease progression results from failures in host control or antibiotic therapy at some tissue sites, despite successful simultaneous eradication in others. Disparate Salmonella-host encounters thus make the difference between lethal disease and successful control.