Bacterial defense systems exhibit synergistic anti-phage activity

• Published in: Cell host & microbe Vol. 32; no. 4; pp. 557 - 572.e6
• Main Authors: Wu, Yi, Garushyants, Sofya K., van den Hurk, Anne, Aparicio-Maldonado, Cristian, Kushwaha, Simran Krishnakant, King, Claire M., Ou, Yaqing, Todeschini, Thomas C., Clokie, Martha R.J., Millard, Andrew D., Gençay, Yilmaz Emre, Koonin, Eugene V., Nobrega, Franklin L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.04.2024
• Subjects: co-occurrence; Druantia; Gabija; ietAS; Kiwa; phylogroups; prokaryotic immunity; Septu; tmn; Zorya; co-occurrence; tmn; phylogroups; Gabija; prokaryotic immunity; Kiwa; Zorya; ietAS; Septu; Druantia
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2024.01.015

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. [Display omitted] •Co-occurring bacterial defense systems display synergistic anti-phage activity•Zorya II synergizes with Druantia III and ietAS, and tmn synergizes with Gabija and Septu I•Tmn synergizes with defense systems containing sensory switch ATPase domains•Active systems recruit functional domains of inactive systems for enhanced efficacy Bacteria defend against phages using a variety of defense systems, yet their interactions are poorly understood. Wu and Garushyants et al. reveal that these defense systems are generally compatible and, in some instances, interact resulting in synergistic anti-phage effects, conferring an evolutionary advantage on bacteria under specific environmental conditions.