Modeling of the ComRS Signaling Pathway Reveals the Limiting Factors Controlling Competence in Streptococcus thermophilus

In streptococci, entry in competence is dictated by ComX abundance. In Streptococcus thermophilus, production of ComX is transient and tightly regulated during growth: it is positively regulated by the cell-cell communication system ComRS during the activation phase and negatively regulated during the shut-off phase by unidentified late competence gene(s). Interestingly, most S. thermophilus strains are not or weakly transformable in permissive growth conditions (i.e., chemically defined medium, CDM), suggesting that some players of the ComRS regulatory pathway are limiting. Here, we combined mathematical modeling and experimental approaches to identify the components of the ComRS system which are critical for both dynamics and amplitude of ComX production in S. thermophilus. We built a deterministic, population-scaled model of the time-course regulation of specific ComX production in CDM growth conditions. Strains LMD-9 and LMG18311 were respectively selected as representative of highly and weakly transformable strains. Results from in silico simulations and in vivo luciferase activities show that ComR concentration is the main limiting factor for the level of comX expression and controls the kinetics of spontaneous competence induction in strain LMD-9. In addition, the model predicts that the poor transformability of strain LMG18311 results from a 10-fold lower comR expression level compared to strain LMD-9. In agreement, comR overexpression in both strains was shown to induce higher competence levels with deregulated kinetics patterns during growth. In conclusion, we propose that the level of ComR production is one important factor that could explain competence heterogeneity among S. thermophilus strains.