Bacteria of the genus Streptomyces undergo a complex life cycle starting from single spores developing into a branched mycelium that is followed by formation of aerial hyphae and maturation of spores. Sporulation and related cell division in Streptomyces is controlled by a regulatory network involving WhiA and WhiB transcriptional regulators, which co-regulate genes critical to development. In this study, we focused on investigating the impact of phage infection on cellular development using the model species Streptomyces venezuelae. We observed that phage infection on solid media triggered the development of aerial hyphae and sporulation at the infection interface of the plaque. Analysis of mutant strains defective at different stages of Streptomyces development further confirmed the importance of cellular development for the establishment of transient phage resistance promoting the containment of viral infections.

Genome analysis of phages infecting actinobacteriophages showed that WhiB-like proteins represent the most abundant transcriptional regulator in these viruses. Specifically, 31 % of phages infecting Streptomyces harbor whiB including many containing further developmentally relevant genes. RT-qPCR reveals early expression of phage-encoded WhiB during infection and global transcriptome analysis suggest a suppression of cellular development in the early stages of infection. Expression of phylogenetically diverse phage-encoded whiB genes in an S. venezuelae ΔwhiB strain are unable to complement the phenotype of this strain. These findings indicate that development is playing an important role during phage infection, both as host-specific phage defense and as target for phage-driven host manipulation. Altogether, our studies emphasize cellular development and the emergence of transient phage resistance as an important layer of Streptomyces antiviral immunity.