Bacterial defense systems exhibit synergistic anti-phage activity
Yi Wu, Sofya K. Garushyants, Anne van den Hurk, Cristian Aparicio-Maldonado, Simran Krishnakant Kushwaha, Claire King, Yaqing Ou, Thomas C. Todeschini, Martha R. J. Clokie, Andrew Millard, Yilmaz Emre Gençay, Eugene V. Koonin, Franklin L. Nóbrega
Abstract
Bacterial defense against phage predation involves diverse defense systems acting individually and concurrently, yet their interactions remain poorly understood. We investigated >100 defense systems in 42,925 bacterial genomes and identified numerous instances of their non-random co-occurrence and negative association. For several pairs of defense systems significantly co-occurring in Escherichia coli strains, we demonstrate synergistic anti-phage activity. Notably, Zorya II synergizes with Druantia III and ietAS defense systems, while tmn exhibits synergy with co-occurring systems Gabija, Septu I, and PrrC. For Gabija, tmn co-opts the sensory switch ATPase domain, enhancing anti-phage activity. Some defense system pairs that are negatively associated in E. coli show synergy and significantly co-occur in other taxa, demonstrating that bacterial immune repertoires are largely shaped by selection for resistance against host-specific phages rather than negative epistasis. Collectively, these findings demonstrate compatibility and synergy between defense systems, allowing bacteria to adopt flexible strategies for phage defense.