Génomique évolutive des systèmes antiphages

Bacteriophages, or phages, are viruses that specifically target bacteria. For billions of years, this interaction has driven a co-evolutionary arms race between phages and bacteria, yielding to numerous bacterial defense mechanisms against phage infections. During my PhD, I focused on studying defense systems: proteins or groups of proteins that disrupt or block phage replication or are released during infection. While anti-phage defense systems had been studied since the 1950s with the discovery of restriction-modification systems, the diversity of known systems remained limited until 2015, when new genomics and experimental methods allowed the discovery and validation of over 100 defense systems. At the start of my PhD, although numerous defense systems had been identified, little was known about their distribution across bacterial species. My research focused on various genomic aspects of anti-phage defense systems. In the first chapter, we investigated the bacterial reservoir of these systems to address key questions: How many defense systems are encoded by each bacterium? What is the abundance of these systems? How are they distributed across bacterial phyla? To answer these, I developed DefenseFinder, a tool designed to systematically detect defense systems. Using this tool, I characterized the defense repertoire of diverse bacteria using a database of publicly available genomes. While bacteria develop defense systems against phages, phages, and mobile genetic elements, in turn, produce anti-defense proteins. In the second chapter, I developed AntiDefenseFinder to explore the diversity of these anti-defense systems, investigating whether specific mobile genetic elements encode particular anti-defense mechanisms. We discovered that certain anti-defense systems are indeed specific to particular types of mobile genetic elements, and we also highlighted that most anti-defense systems remain unknown. Third, we observed that bacteria frequently encode multiple defense systems in their genomes and explored why bacteria accumulate defense systems in their genomes. By analyzing bacteria-phage interactions at the genus level, we demonstrated that an increase in defense systems in Escherichia does not necessarily correlate with broader protection against phages. Lastly, we examined the evolutionary dynamics of proteins within defense systems. Through genomic analysis, we identified and characterized a family of lanthipeptides (biosynthetic gene clusters) with anti-phage activity, showing that a specific clade evolved into a defense system. During my PhD, I explored the genomics of bacterial anti-phage defense systems, focusing on their diversity, distribution, and evolution. I developed two tools to systematically identify and characterize both defense and anti-defense systems within genomes, providing new insights into their abundance and distribution across different microbial species. My research also investigated the accumulation of these defense systems in bacteria, their significance in natural isolates, and the evolutionary history of a particular protein family with anti-phage activity. This work paves the way for a deeper understanding of the diversity, distribution, and evolutionary dynamics of bacterial anti-phage defense systems, providing tools and insights that will aid future research on the arms race between bacteria and phages.