Generalist and human-restricted Salmonella evolved divergent human intestinal epithelial cell tropism

Generalist and human-restricted Salmonella enterica serovars cause diseases ranging from gastroenteritis to typhoid fever. Using live-imaging with controlled-polarity human intestinal epithelial cell (IEC) organoids, we identify epithelial cell sensing as a pre-invasion stage of infection. The generalist serovar Typhimurium migrates toward apical but away from basolateral IEC surfaces, whereas the human-restricted serovar Typhi exhibits the opposite behavior. This polarized tropism is coordinated by signaling between the Aer and Tcp chemoreceptors. Tcp senses citrate released from apical IEC surfaces, while Aer differentially integrates this signal. A single conserved, serovar-specific residue in Aer determines whether Tcp-dependent citrate sensing promotes attraction or repulsion. This pre-invasion stage directs Salmonella to IEC surfaces permissive for invasion and contributes to distinct invasion outcomes. Our findings define a serovar-specific strategy for IEC surface recognition and provide mechanistic insight into how S. Typhimurium and S. Typhi differentially initiate interactions with the human intestinal epithelium. Generalist and human-restricted Salmonella enterica serovars cause gastroenteritis and typhoid fever, respectively. Here, McKenna et al. show that the two types of serovars use opposing pre-invasion strategies to sense and invade human intestinal epithelium.