Population analysis of Legionella pneumophila reveals the basis of resistance to complement-mediated killing

is the most common cause of the severe respiratory infection known as Legionnaires’ disease. is typically a symbiont of free-living amoeba, and our understanding of the bacterial factors that determine human pathogenicity is limited. Here we carried out a population genomic study of 900 isolates from human clinical and environmental samples to examine their genetic diversity, global distribution and the basis for human pathogenicity. We found that although some clones are more commonly associated with clinical infections, the capacity for human disease is representative of the breadth of species diversity. To investigate the bacterial genetic basis for human disease potential, we carried out a genome-wide association study that identified a single gene (), to be most strongly associated with clinical isolates. Molecular evolutionary analysis showed that , which encodes an -acetyltransferase responsible for lipopolysaccharide modification, has been distributed horizontally across all major phylogenetic clades of by frequent recent recombination events. Functional analysis revealed a correlation between the presence of a functional gene and resistance to killing in human serum and bovine broncho-alveolar lavage. In addition, strains that express escaped complement-mediated phagocytosis by neutrophils. Importantly, we discovered that the expression of confers the capacity to evade complement-mediated killing by inhibiting deposition of classical pathway molecules on the bacterial surface. In summary, our combined population and functional analyses identified genetic traits linked to human disease and revealed the molecular basis for resistance to complement-mediated killing, a previously elusive trait of direct relevance to human disease pathogenicity.