A prophage competition element protects Salmonella from lysis.

Most bacteria are polylysogens that carry multiple prophages integrated into the chromosome. These prophages confer advantages to their bacterial host, yet also pose a lethal threat as they can reactivate and enter a lytic cycle. DNA damage of the bacterial host is a common trigger of prophage lytic cycles. Because DNA damage is frequently experienced by bacterial pathogens exposed to host immune defenses, prophage activation may be common during infection. Investigating the consequences of prophage induction in Salmonella, we discover a prophage competition element in the Gifsy-1 prophage that we name ribonuclease effector module with ATPase, inhibitor, and nuclease (RemAIN) because it blocks the lytic cycles and release of viral particles of co-resident prophages. Intramacrophage Salmonella persisters, a subpopulation that incurs DNA damage, experience prophage reactivation and subsequent RemAIN activation, which influences Salmonella persisters and macrophage response to infection. Our findings reveal a multi-layered host-pathogen arms race in which prophage-prophage competition influences bacterial persistence and the mammalian immune response.