Genetic and molecular determinants of polymicrobial interactions in <i>Fusobacterium nucleatum</i>

Significance Fusobacterium nucleatum interacts with many oral microbes and has the ability to spread to the placenta and amniotic fluid, promoting preterm birth. Yet, the molecular mechanisms underlying polymicrobial interactions, termed coaggregation, by Fusobacteria are poorly understood. Here, we revealed that the two-component signal transduction system CarRS regulates expression of genes encoding lysine utilization factors (e.g., KamA) and the coaggregation factor RadD. Extracellular lysine blocks RadD-mediated coaggregation by binding to RadD. Significantly, mutants lacking KamA or CarR (which up-regulates RadD) are attenuated in virulence in a preterm birth model, while mutants devoid of RadD or CarS (which down-regulates RadD) exhibit increased virulence. Our findings unveiled a molecular linkage between coaggregation and lysine metabolism via CarRS-mediated gene regulation that modulates bacterial virulence.