Characterization of the Trehalose Utilization Operon in Streptococcus mutans Reveals that the TreR Transcriptional Regulator Is Involved in Stress Response Pathways and Toxin Production

Streptococcus mutans , the organism most frequently associated with the development of dental caries, is able to utilize a diverse array of carbohydrates for energy metabolism. One such molecule is trehalose, a disaccharide common in human foods, which has been recently implicated in enhancing the virulence of epidemic strains of the pathogenClostridium difficile . In this study, mutants with deletions of all three genes in the putativeS. mutans trehalose utilization operon were characterized, and the genes were shown to be required for wild-type levels of growth when trehalose was the only carbohydrate source provided. Interestingly, the TreR transcriptional regulator appeared to be critical for responding to oxidative stress and for mounting a protective stress tolerance response following growth at moderately acidic pH. mRNA sequencing (RNA-seq) of atreR deletion mutant suggested that inS. mutans , TreR acts as a trehalose-sensing activator of transcription of thetre operon, rather than as a repressor, as described in other species. In addition, deletion oftreR caused the downregulation of a number of genes involved in genetic competence and bacteriocin production, supporting the results of a recent study linking trehalose and theS. mutans competence pathways. Finally, deletion oftreR compromised the ability ofS. mutans to inhibit the growth of the competing speciesStreptococcus gordonii andLactococcus lactis . Taking the results together, this study solidifies the role of theS. mutans tre operon in trehalose utilization and suggests novel functions for the TreR regulator, including roles in the stress response and competitive fitness.IMPORTANCE S. mutans is the primary etiologic agent of dental caries, which globally is the most common chronic disease.S. mutans must be able to outcompete commensal organisms in its dental plaque niche in order to establish persistence and pathogenesis. To that end,S. mutans metabolizes a diverse array of carbohydrates to generate acid and impede its acid-sensitive neighbors. Additionally,S. mutans utilizes quorum signaling through genetic competence-associated pathways to induce production of toxins to kill its rivals. This study definitively shows that theS. mutans trehalose utilization operon is required for growth in trehalose. Furthermore, this study suggests that theS. mutans TreR transcriptional regulator has a novel role in virulence through regulation of genes involved in genetic competence and toxin production.