experimental and bioinformatic data

Bacterial defence against phage predation involves diverse immune systems acting both individually and concurrently, yet their interactions remain poorly understood. We investigated co-occurrence of 110 immune systems in 26,362 <i>Escherichia coli</i> genomes and identified numerous instances of co-occurrence and mutual exclusion. Co-occurrence of immune systems does not strongly correlate with co-localisation in the genome, and thus does not seem to be caused primarily by concurrent horizontal gene transfer. For several co-occurring pairs, we demonstrate synergistic anti-phage activity <i>in vivo</i>, with tmn synergising with immune systems containing sensory switch ATPase domains. Pairs of mutually exclusive immune systems in <i>E. coli</i> co-occur in other taxa, with one pair showing synergy, suggesting that evolution of immune repertoires is shaped by selection for robust phage resistance rather than by negative epistasis. Our findings demonstrate compatibility and synergy between immune systems, allowing bacteria to adopt flexible strategies for phage defence, driven by unique environmental pressures.