Horizontally Acquired Biosynthesis Genes Boost Coxiella burnetii's Physiology

Abstract

<i>Coxiella burnetii</i>, the etiologic agent of acute Q fever and chronic endocarditis, has a unique biphasic life cycle, which includes a metabolically active intracellular form that occupies a large lysosome-derived acidic vacuole. <i>C. burnetii</i> is the only bacterium known to thrive within such an hostile intracellular niche, and this ability is fundamental to its pathogenicity; however, very little is known about genes that facilitate <i>Coxiella</i>'s intracellular growth. Recent studies indicate that <i>C. burnetii</i> evolved from a tick-associated ancestor and that the metabolic capabilities of <i>C. burnetii</i> are different from that of <i>Coxiella</i>-like bacteria found in ticks. Horizontally acquired genes that allow <i>C. burnetii</i> to infect and grow within mammalian cells likely facilitated the host shift; however, because of its obligate intracellular replication, <i>C. burnetii</i> would have lost most genes that have been rendered redundant due to the availability of metabolites within the host cell. Based on these observations, we reasoned that horizontally derived biosynthetic genes that have been retained in the reduced genome of <i>C. burnetii</i> are ideal candidates to begin to uncover its intracellular metabolic requirements. Our analyses identified a large number of putative foreign-origin genes in <i>C. burnetii</i>, including tRNA^Glu2 that is potentially required for heme biosynthesis, and genes involved in the production of lipopolysaccharide-a virulence factor, and of critical metabolites such as fatty acids and biotin. In comparison to wild-type <i>C. burnetii</i>, a strain that lacks tRNA^Glu2 exhibited reduced growth, indicating its importance to <i>Coxiella</i>'s physiology. Additionally, by using chemical agents that block heme and biotin biosyntheses, we show that these pathways are promising targets for the development of new anti-<i>Coxiella</i> therapies.