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Abstract

Quorum Sensing (QS) is a form of cell-to-cell communication that allows bacteria to detect and interpret chemical signals to dynamically modify their behaviour in response to bacterial population density. This is achieved through the production of small diffusible molecules known as autoinducers (AIs) such as N-acyl-homoserine lactones (AHLs) or autoinducer-2 (AI-2). Despite the wealth of knowledge about QS systems in both Gram-positive and Gram-negative bacteria, there is still little known about the repertoire of QS-signals used by bacterial species derived from the gastrointestinal tract. To expand our understanding of QS regulation by gastrointestinal pathogens we focused on Citrobacter rodentium, a natural murine pathogen sharing key virulence strategies and disease outcomes with human pathogens enteropathogenic and enterohemorrhagic Escherichia coli (EPEC, EHEC). Using a LC-MS/MS approach, we identified three QS molecules that are produced by C. rodentium and profiled them over time both in vitro and in vivo during infection of mice. We also explored the role of the two AHL-mediated QS systems (CroIR and SdiA) present in C. rodentium and demonstrated how these systems enable the pathogen to fine-tune the expression of virulence machinery and improve bacterial fitness during infection. Importantly, we also showed that mice infected with a ΔcroI or a ΔsdiA mutant strain displayed increased morbidity and mortality as compared to mice infected with wild-type C. rodentium. These findings highlight the importance of QS as a key regulator of virulence. As the manipulation of QS has been suggested as a therapeutic intervention for pathogen infection, these results also demonstrate the need for development of pathogen-specific interventions. To further expand our knowledge about QS communication in the gastrointestinal tract we screened over 100 bacterial isolates for QS activity by using multiple biosensor-based assays optimized for efficient screening of AI-2 as well as short-, medium-, and long-chain AHLs. We identified 64 species that induced an AI-2 like activity and 9 that were capable of inducing an AHL like activity. Overall, this works expands our understanding about the small-molecule dependent interactions that occur in the gastrointestinal tract, with the potential to aid in the design of novel QS-based therapeutic strategies.