The Typhi colonization factor (Tcf) is encoded by multiple non-typhoidal Salmonella serovars but exhibits a varying expression profile and interchanging contribution to intestinal colonization.

Salmonella enterica serovars Typhi and Paratyphi A are human-restricted pathogens and the leading causative agents of enteric fever. The Typhi colonization factor (Tcf) is a chaperone-usher fimbria, thought to play a role in the host-specificity of typhoidal serovars. Here we show that the tcf cluster (tcfABCD tinR tioA) is present in at least 25 non-typhoidal Salmonella (NTS) serovars and demonstrate its native expression in clinically-important serovars including Schwarzengrund, 9,12:l,v:-, Choleraesuis, Bredeney, Heidelberg, Montevideo, Virchow and Infantis. Although the genetic organization of the tcf cluster is well conserved, the N-terminal half of the fimbrial adhesin, TcfD is highly diverse, suggesting different binding properties of distinct tcfD variants. Comparison of tcfA expression in typhoidal and NTS serovars demonstrated unexpected differences in its expression profiles, with the highest transcription levels in S. Typhi, S. Choleraesuis and S. Infantis. In the latter, tcf is induced in rich broth and under microaerobic conditions, characterizing the intestines of warm blooded animals. Furthermore, Tcf is negatively regulated by the ancestral leucine-responsive transcriptional regulator (Lrp). Using the colitis mouse model, we demonstrate that during mice infection tcfA is expressed at higher levels by S. Infantis than S. Schwarzengrund or S. Heidelberg. Moreover, while Tcf is dispensable for S. Schwarzengrund and S. Heidelberg mouse colonization, Tcf is involved in cecum and colon colonization by S. Infantis. Taken together, our results establish that Tcf is broadly encoded by multiple NTS serovars, but presents variable expression profiles and contributes differently to their virulence.