Abstract

Coxiella burnetii, 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. C. burnetii 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 Coxiella's intracellular growth. Recent studies indicate that C. burnetii evolved from a tick-associated ancestor and that the metabolic capabilities of C. burnetii are different from that of Coxiella-like bacteria found in ticks. Horizontally acquired genes that allow C. burnetii to infect and grow within mammalian cells likely facilitated the host shift; however, because of its obligate intracellular replication, C. burnetii 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 C. burnetii are ideal candidates to begin to uncover its intracellular metabolic requirements. Our analyses identified a large number of putative foreign-origin genes in C. burnetii, including tRNAGlu2 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 C. burnetii, a strain that lacks tRNAGlu2 exhibited reduced growth, indicating its importance to Coxiella'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-Coxiella therapies.

Highlights

  • Coxiella burnetii is the etiological agent of acute Q fever and a chronic disease commonly manifested as endocarditis (Maurin and Raoult, 1999)

  • We identified a large number of horizontally derived genes, including those for the synthesis of LPS, fatty acids, heme, and biotin that augment the physiological capability of C. burnetii

  • By examining differences in nucleotide composition (e.g., GC%) horizontal gene transfer (HGT)-origin genes can be tentatively identified; because most transfers occur between closely related bacteria, and because genes from distant organisms will evolve over time to reflect the base composition of the recipient genome (Lawrence and Ochman, 1997), this approach is not always effective

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Summary

Introduction

Coxiella burnetii is the etiological agent of acute Q fever and a chronic disease commonly manifested as endocarditis (Maurin and Raoult, 1999). Coxiella-like bacteria found in ticks cannot infect mammalian cells and are unable to grow in ACCM-2, a culture medium that supports robust growth of C. burnetii (Omsland et al, 2011; Duron et al, 2015).

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