SUMMARY
Bacteria utilize CRISPR-Cas adaptive immune systems for protection from bacteriophages (phages), and some phages produce anti-CRISPR (Acr) proteins that inhibit immune function. Despite thorough mechanistic and structural information describing the mode-of-action for Acr proteins, how they are deployed by phages during infection is unknown. Here, we show that Acr production does not guarantee phage replication, but instead, CRISPR-Cas neutralization and phage infections fail when phage population numbers are too low. Failing infections can be rescued by kin phages acting as Acr producers, demonstrating that infections succeed if a sufficient Acr dose is contributed to a single cell by multiple phage genomes. The production of Acr proteins by phage genomes that fail to replicate leave the cell immunosuppressed, assisting other phages in the population. These observations apply generally to both Cas3 and Cas9-based adaptive immunity. This “cooperative phage” mechanism for CRISPR-Cas inhibition demonstrates inter-virus cooperation that may find parallels in other host-parasite interactions.