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Abstract:

Bacteria possess multiple lines of defense to resist bacteriophage infection. Currently, more than 150 bacterial anti-phage defense systems are known that widely differ in their modes of action. A bacterial genome carries, on average, 5 distinct (currently identifiable) defense systems. The remarkable variability of immune repertoires has been observed even within the same species. Although the mechanisms of action for individual systems have been extensively studied, the interactions between systems remain poorly understood. We investigated the co-occurrence of defense systems in 26,362 Escherichia coli genomes, as well as in complete genomes from four bacterial orders, Enterobacterales, Bacillales, Burkholderiales, and Pseudomonadales, to gain insight into the role of interactions between different defense systems in anti-phage immunity. Our findings show that defense system co-occurrence varies across E. coli phylogroups and taxa, and is not directly related to the genomic co-localisation of the genes encoding the co-occurring systems. For several pairs of non-randomly co-occurring and negatively associated defense systems in E. coli, we experimentally demonstrated synergistic interactions that provided an evolutionary advantage to the bacterial population. Moreover, some of the defense systems that are negatively associated in E. coli were found to co-occur in other bacterial taxa and can also protect synergistically against specific phages. Our findings imply that the evolution of bacterial immune repertoires is shaped largely by selection for resistance to host-specific phages that can be enhanced by cooperation between different defense systems rather than by negative epistasis.