Mechanisms of Integrative and Conjugative Elements in Oral Bacteria

Streptococcus mutans resides in the oral cavity where it is known to initiate the development of dental caries (tooth decay). For this pathogen to thrive in the dynamic and variable environment of the mouth it must be adaptable both to short- and long-term ecological pressures. The horizontal acquisition of new DNA, which may encode for new beneficial traits, is a critical aspect of S. mutans adaptability. In addition, regulation of the processes involved in the acquisition of DNA are intertwined with the basic physiology and stress responses of S. mutans. In recent work supported by R03 DE029882, we investigated an integrative and conjugative element (ICE) carried by S. mutans. ICEs are mobile elements that are integrated on the genome and possess the ability to transfer to nearby bacteria via conjugation. Importantly, these elements can transfer new traits to bacteria, and this can spread genes related to antibiotic resistance, metabolism, and virulence. We have discovered several notable features of this ICE, including a potentially sophisticated regulatory system and that activation has critical effects on S. mutans physiology. Despite ICEs being frequently present on bacterial genomes, studies of their molecular mechanisms are lacking and very little is known about ICEs in oral bacteria. It is therefore a high priority to understand how these gene transfer systems are activated/regulated, how they impact host physiology, and how they could spread traits among oral bacteria. To address this, we have developed three Specific Aims: Aim 1: Dissect the regulatory mechanisms that control the switch from the integrated to excised state of TnSmu1; Aim 2: Examine TnSmu1-mediated phenotypic heterogeneity including mechanisms of a growth arrest outcome; and Aim 3: Analysis of ICE transfer between bacteria in biofilm communities. Taken together, the information derived from these studies will provide a wealth of new knowledge for an unexplored mechanism of gene transfer in the oral microbiome. It is anticipated that the results will provide novel insights into the functioning of the ICE carried by S. mutans, and that these insights will have a broader impact on our knowledge of ICEs carried by other oral bacteria. Elucidation of how these gene transfer systems work is critical for a deeper understanding of pathogen adaptability and then harnessing this knowledge to develop more comprehensive strategies to eliminate disease. Project Number: 7R01DE033403-03 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Robert Shields (+1 co-PI) | Institution: UNIVERSITY OF FLORIDA, GAINESVILLE, FL | Award Amount: $374,511 | Activity Code: R01 | Study Section: Oral, Dental and Craniofacial Sciences Study Section[ODCS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11335370