SdiA Bridges Chemical Signaling between Salmonella enterica Serovar Typhimurium and Yersinia enterocolitica in Mice

The role of SdiA quorum-sensing-mediated signaling in Salmonella enterica serovar Typhimurium has been a matter of debate for many years. Although Salmonella harbors SdiA, it does not produce an acyl homoserine lactone (AHL) signal (8, 13). Many of the phenotypes associated with SdiA have been shown using sdiA cloned in multicopy plasmids (14). The precise role of SdiA in quorum sensing was elusive for several years until Michael et al. (8) reported that SdiA is not sensing an autoinducer produced by Salmonella itself but rather AHLs produced by other bacterial species. These authors also reported that SdiA-dependent phenotypes could be observed only in the presence of AHLs. These results are consistent with reports that most LuxR-type proteins use the AHL autoinducer as a “cofactor” to allow proper protein folding and that in the absence of this signal, the protein is targeted to degradation (10, 16, 17). The nuclear magnetic resonance structure of the SdiA protein has been solved and shows that SdiA uses AHL as a folding switch and requires binding of this signal to allow proper protein folding (15). SdiA regulates a few genes in Salmonella, including one gene involved in resistance to human complement, rck, and a predicted type III secreted effector, srgE (2). However, mutation of the sdiA gene had no effect on virulence of Salmonella in mouse, chicken, or bovine models of disease (1). This lack of phenotypes “in vivo” could be a result of Salmonella not encountering AHLs in these infection models. The first clue that this might be the case occurred when it was found that turtles colonized by Aeromonas hydrophila (a bacterium that produces AHLs) activated SdiA function in these animals (12). Now Dyszel et al. (5) have shown that in mice coinfected with Salmonella serovar Typhimurium and Yersinia enterocolitica (an enteric bacterium that produces AHLs), SdiA is activated. Although SdiA did not confer an advantage to Salmonella colonization over that of Yersinia, a Salmonella strain engineered to produce AHLs has a colonization advantage over an sdiA mutant in competition assays using mice. The difference in these outcomes could be the result of a transient interaction between Salmonella and Yersinia during coinfection, not allowing a full effect of SdiA signaling to be detected in Salmonella colonization. Meanwhile, constant AHL production in the engineered Salmonella strain allows a colonization phenotype during murine infection. This study indicates for the first time that SdiA is functional during murine infection in the presence of AHLs. Quorum sensing was first described for the regulation of bioluminescence in Vibrio fischeri (9). The luciferase operon in Vibrio fischeri is regulated by two proteins, LuxI, which is responsible for the production of the acyl-homoserine-lactone (AHL) autoinducer, and LuxR, which is activated by this autoinducer to increase transcription of the luciferase operon (6, 7). Since this initial description, homologues of LuxR-LuxI have been identified in other bacteria, and in all of these LuxR-LuxI systems, the bacteria produce an AHL autoinducer, which binds to the LuxR protein and regulates the transcription of several genes involved in a variety of phenotypes. These include the production of antibiotics in Erwinia, motility in Yersinia pseudotuberculosis, and pathogenesis and biofilm formation in Pseudomonas aeruginosa, among others (3, 4, 11). Escherichia coli and Salmonella have a LuxR homologue, SdiA (14), but do not have a luxI gene and do not produce AHLs (8, 13). The E. coli sdiA gene initially was isolated as a regulator of the cell division genes ftsQAZ (14). However, whether SdiA was indeed an AHL sensor was a matter of debate until Michael et al. (8) reported that SdiA is not sensing an autoinducer produced by Salmonella itself but AHLs produced by other bacterial species. This observation makes sense when one considers that unlike Vibrio fischeri, which is in pure culture within the light organ of fish and squids, Salmonella and E. coli are enteric bacteria that colonize the intestine of animals together with many other bacterial species that compose the microbial flora. In this groundbreaking article, Dyszel et al. (5) show that Salmonella SdiA is functional during murine infection when AHLs are present and that SdiA-regulated genes are involved in enhancing Salmonella's colonization of the intestine. Although SdiA is not functional during murine infection with just Salmonella, it is functional during coinfection with an AHL-producing pathogen, Yersinia enterocolitica. This study highlights that coinfection with different pathogens may lead to different outcomes because of cross-chemical communication between different bacterial species.