Community-level diversity of viral counter-defensomes

Bacteria and phages have co-evolved tit-for-tat strategies to combat one another for survival. To overcome phage infection, bacteria have developed various defense systems (the defensome), and in response, phages have evolved a counter-defensome to inhibit or evade such defensive strategies. While significant progress has been achieved on mechanistic, structural and functional aspects of the defensome, the study of the phage counter-defensome is relatively new, with very limited information available on the diversity and distribution of these systems across complex environmental phageomes. Here we present a large-scale analysis of the counter-defensome of 50,595 DNA phage population genomes reconstructed from soil, marine, and human gut environments. We observed substantial variation in the frequency and composition of the counter-defensome across phage families, which correlated with host range, habitat, and geographic context. A substantial fraction of the counter-defensome was clustered in islands, with gene expression restricted to a limited subset of families. Moreover, both phage counter-defense and bacterial-type defense families were detected across genomes of nucleocytoplasmic large DNA viruses, suggesting cross-clade horizontal gene transfer. Our results reveal the diverse counter-defense strategies across environmentally distinct viral communities and provide a foundation for uncovering novel mechanisms that shape conflicts and alliances in host–virus immunity networks.