Horizontally acquired biosynthesis genes boost Coxiella burnetii’s physiology

<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 a hostile intracellular niche, and this ability is fundamental to its pathogenicity; however, very little is known about genes that facilitate <i>C. burnetii</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 coxiellae 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 those involved in the biosynthesis of lipopolysaccharide — a virulence factor, and of critical metabolites such as fatty acids and heme. In comparison to wildtype <i>C. burnetii</i>, strains that contained transposon insertions or deletions in several of these genes exhibited reduced growth, signifying their importance to <i>Coxiella</i>’s physiology. Additionally, by using chemical agents that block heme biosyntheses, we show that these pathways are promising targets for the development of new anti-<i>Coxiella</i> therapies. These findings are significant because current antibiotics are not very effective against chronic endocarditis caused by <i>C. burnetii</i>, and because resistance to currently available antibiotics is prevalent among clinical strains.