Abstract

Both symbiotic and pathogenic bacteria in the family Coxiellaceae causemorbidity andmortality in humans and animals. For instance, Coxiella-like endosymbionts (CLEs) improve the reproductive success of ticks a major disease vector, while Coxiella burnetii causes humanQfever, and uncharacterized coxiellae infect both animals andhumans. To better understand the evolution of pathogenesis and symbiosis inthisgroupof intracellularbacteria,we sequencedthegenomeof aCLEpresent inthe soft tickOrnithodoros amblus (CLEOA) andcomparedit tothegenomesofotherbacteria in theorder Legionellales.Ouranalyses confirmedthatCLEOAismoreclosely relatedto C. burnetii, the human pathogen, than to CLEs in hard ticks, and showed that most clades of CLEs contain both endosymbionts and pathogens, indicating that severalCLE lineages have evolved independently frompathogenic Coxiella.We also determined that the last common ancestorof CLEOA and C. burnetiiwas equipped to infect macrophages and that even though horizontal gene transfer (HGT) contributed significantly to the evolution of C. burnetii,most acquisition events occurred primarily in ancestors predating the CLEOA C. burnetii divergence. These discoveries clarify the evolution of C. burnetii, which previously was assumed to have emerged when an avirulent tick endosymbiont recently gained virulence factors viaHGT. Finally,we identified severalmetabolic pathways, including heme biosynthesis, that are likely critical to the intracellular growth of thehuman pathogen but not the tick symbiont, and showthat the use of heme analog is a promising approach to controlling C. burnetii infections.