PHAGECOUNTER · Discovery of counter defense strategies of bacteriophages against bacterial immunity

Discovery of counter defense strategies of bacteriophages against bacterial immunity

Our planet is truly microbial, with microbes driving essential functions across all ecosystems. But what impacts microbes most profoundly are their viruses—bacteriophages, or simply phages. When phages infect bacteria, the microbial hosts fight back using highly complex immune systems. The field of bacterial immunity has recently witnessed a surge of groundbreaking discoveries, with more than 200 different defense system types discovered over the last 5 years. It is now evident that bacterial viruses carry an arsenal of anti-defense strategies to neutralize bacterial defense systems, with the greatest diversity in their direct inhibitors. For a long time, research focused almost exclusively on anti-restriction-modification (anti-RM) and anti-CRISPR proteins, and despite recent discoveries expanding the known repertoire of inhibitors, these have so far been identified for only about 10% of all defense system types. The diversity, distribution, and genomic organization of anti-defense systems remain largely unexplored. Because these proteins are small and fast-evolving, they often escape detection by traditional bioinformatics. To address this gap, my project developed a machine learning–based approach to systematically discover anti-defense proteins. This strategy enabled me to pursue three key objectives: (1) to identify a broad diversity of anti-defense proteins of phages, (2) validate their anti-defense properties, and (3) characterize a novel feature of anti-defense proteins – their broad specificity. This work provides the first systematic framework for uncovering the hidden diversity of anti-defense systems and reveals new molecular strategies used by phages to overcome bacterial immunity. By identifying inhibitors with broad specificity, it also opens the door to understanding how phages adapt to diverse bacterial hosts and immune landscapes. These insights have broad implications for microbial ecology, phage therapy, and biotechnology, where modulating bacterial immunity is of growing interest. This research holds great promise for improving phage therapy, a promising alternative to antibiotic resistance.

Data: CORDIS, © European Union