Interspecies quorum sensing signals Vibrio cholerae to modulate its multicellular organization and enhance contact-dependent antagonism

Spatial organization within bacterial communities plays a critical role in mediating cell-cell interactions and determining microbial fitness. During infection, Vibrio cholerae undergoes dynamic restructuring of its spatial organization, forming monospecific aggregates thought to enhance survival in the face of the host immune system. However, the effectiveness of its primary weapon against other bacteria—its contact-dependent type VI secretion system (T6SS)—is severely limited in this aggregated form, hampering its ability to compete for space and resources. Here, we show that the presence of competing, co-resident bacteria alter V. cholerae aggregation by modulating toxin co-regulated pilus (TCP) expression through production of interspecies quorum sensing signal autoinducer-2 (AI-2). Using a zebrafish infection model, we found that this quorum sensing-controlled disaggregation enhances the efficacy of T6SS-mediated killing in vivo by promoting intermixing of V. cholerae, thereby increasing cell-cell contact with competitors. This modulation of aggregation has no impact on T6SS activity in vitro, highlighting the context-specific nature of these interactions. We developed a mathematical model to explore these dynamics and observed a fundamental trade-off between potency of V. cholerae T6SS and its sensitivity to the presence of competing bacterial species. Our findings reveal a core mechanism underlying V. cholerae colonization wherein it uses quorum sensing to dynamically balance between protective aggregation to survive host defenses and dispersed infiltrative intermixing to facilitate elimination of competitors.