VicRK and LiaSR Two-Component Systems Exhibit Extensive Crosstalk Regulating *S. mutans* Virulence and Biofilm Formation

Dental caries and persistent endodontic infections remain significant global health challenges, largely driven by Streptococcus mutans's ability to form acidogenic, aciduric, and therapeutically recalcitrant biofilms. Current antimicrobial strategies often lead to resistance and adverse side effects. The VicRK and LiaSR two-component signal transduction systems (TCS) are crucial regulators of S. mutans virulence, envelope integrity, and stress response, making them attractive targets for novel anti-virulence therapeutics that could circumvent traditional resistance mechanisms.

This comprehensive review synthesized updated evidence from molecular, genetic, and systems-level studies to elucidate the architecture, regulation, and integration of the VicRK and LiaSR two-component systems in controlling S. mutans pathogenicity. The authors analyzed findings from various research methodologies, including structural studies, transcriptomic and proteomic analyses, as well as mutant, knockout, and multi-omics investigations. The focus was on understanding how these systems interact to influence biofilm formation, stress response, and antimicrobial tolerance.

The review revealed that the VicRK and LiaSR two-component systems exhibit extensive regulatory overlap, playing critical roles in S. mutans's ability to survive diverse environmental stresses and form robust biofilms. VicRK is essential for synthesizing molecules crucial for biofilm formation and mitigating environmental stress, while LiaSR responds to antimicrobial peptides, oxidative stress, detergents, and root canal irrigants by activating membrane repair and protective stress pathways. Structural, transcriptomic, and proteomic studies indicate shared regulatory mechanisms, including overlapping promoter targets, cross-phosphorylation, and coordinate regulation of autolysins, cell wall biosynthetic enzymes, and extracellular DNA (eDNA) release. These integrated systems are critical for biofilm formation, EPS structures, antimicrobial tolerance, and interspecies interactions, including synergistic virulence in mixed-species biofilms.

Mutant, knockout, and multi-omics studies consistently demonstrate that both VicRK and LiaSR are indispensable for S. mutans's survival under varying pH, oxidative bursts, nutrient scarcity, and chemical disinfection.