Anti-phage islands force their target phage to directly mediate island excision and spread

Abstract

To defend against their adversaries, bacteria and phage engage in cycles of adaptation and counter-adaptation that shape their mutual evolution1-3. Vibrio cholerae, the causative agent of the diarrheal disease cholera, is antagonized by phages in the environment as well as in human hosts4,5. The lytic phage ICP1 has been recovered from cholera patient stool and water samples over at least 12 years in Bangladesh6-8 and is consequently considered a persistent predator of epidemic V. cholerae in this region. In previous work, we demonstrated that mobile genetic elements called phage-inducible chromosomal island-like elements (PLEs) protect V. cholerae from ICP1 infection7,9. PLEs initiate their anti-phage response by excising from the chromosome, however, the mechanism and molecular specificity underlying this response are not known. Here, we show that PLE 1 encodes a large serine recombinase, Int, that exploits an ICP1-specific protein, PexA, as a recombination directionality factor (RDF) to sense and excise in response to ICP1 infection. We validate the functionality and specificity of this unique recombination system, in which the recombinase and RDF are encoded in separate genomes. Additionally, we show that PexA is also hijacked to trigger excision in PLEs found in V. cholerae isolates recovered decades ago. Our results uncover an aspect of the molecular specificity underlying the longstanding conflict between a single predatory phage and V. cholerae PLE and contribute to our understanding of the molecular arms race that drives long-term evolution between combatting phage and their bacterial hosts in nature.