Systematic reconstruction of an effector-gene network reveals determinants of Salmonella cellular and tissue tropism

Highlights

• Genome reconstruction reveals essential SPI-2 effector genes of Salmonella

• A five-gene network (θ genes) coordinates SCV division and Salmonella proliferation

• θ genes and the spv operon cooperate to induce typhoid fever in mice

• Host-tissue tropism is determined by diverse effector-gene networks

Summary

The minimal genetic requirements for microbes to survive within multiorganism communities, including host-pathogen interactions, remain poorly understood. Here, we combined targeted gene mutagenesis with phenotype-guided genetic reassembly to identify a cooperative network of SPI-2 T3SS effector genes that are sufficient for Salmonella Typhimurium (STm) to cause disease in a natural host organism. Five SPI-2 effector genes support pathogen survival within the host cell cytoplasm by coordinating bacterial replication with Salmonella-containing vacuole (SCV) division. Unexpectedly, this minimal genetic repertoire does not support STm systemic infection of mice. In vivo screening revealed a second effector-gene network, encoded by the spv operon, that expands the life cycle of STm from growth in cells to deep-tissue colonization in a murine model of typhoid fever. Comparison between Salmonella infection models suggests how cooperation between effector genes drives tissue tropism in a pathogen group.