Genus Xenorhabdus (Enterobacteriaceae) consists of bacterial symbionts of soil entomopathogenic nematodes belonging to the genus Steinernema. The symbiotic association represents an insecticidal complex against a wide range of insect pests. Xenorhabdus is also considered as an entomopathogenic bacterium since it kills insects when it is directly injected into insect hemolymph. In the genus Xenorhabdus, only mutants defective for global regulators were totally impaired in virulence, suggesting that weapons of virulence are multiple and redundant (1). We initiated a global approach to identify integrated functions involved in bacterial adaptation to insects and to describe evolutionary history of the virulence/host adaptation factors in Xenorhabdus. We conducted a thorough comparative analysis of several Xenorhabdus strains by undergoing a pathology survey of our Xenorhabdus collection and by sequencing genomes of strains of interest in order to carry out comparative genomics. We identified strains that are non virulent by injection into two lepidopteran model insects, Galleria mellonella (sensitive insect), Spodoptera littoralis (resistant insect). We showed that Xenorhabdus genomes present an important flexible genome (40-50% of the whole genome), organized in functional genomic modules that undergo shuffling (2). We then focused our genomic analysis on two Xenorhabdus species. In Xenorhabdus poinarii, all the strains are attenuated in virulence and display genome reduction (3). In Xenorhabdus bovienii, one non-virulent strain display a genomic expansion and pseudogenization of of some virulence gene (4). We proposed several evolutionary scenarios that may explain the non-virulence of these bacterial strains. References : (1) Nielsen-LeRoux et al. (2012). Curr Opin Microbiol 15: 220–231. (2) Ogier J-C, et al. (2010). BMC Genomics 11: 568. (3) Ogier J-C, et al. (2014). Genome Biol Evol 6: 1495–1513. (4) Bisch G, et al. (2014). J Invertebr Pathol. 124: 15–22.