Molecular pathogenesis of Coxiella burnetii in a genomics era

The agent of acute and chronic Q fever, Coxiella burnetii, occupies a unique niche among intracellular pathogens. The mechanisms the organism employs to cause disease are unclear but involve persistence in a parasitophorous vacuole and the subsequent host response. Studies designed to model molecular mechanisms of pathogenesis have relied upon indirect evidence for testing the role of virulence factors since methods for generation of defined mutations have not been developed. Evidence suggests replication involving a developmental lifecycle is critical for intra- and extracellular survival but this cycle is incompletely defined. It has been proposed that survival in the phagolysosomal-like parasitophorous vacuole requires specific iron uptake systems, secretion of enzymes to detoxify the compartment (catalase and SOD), and down-regulation of an oxidative burst (acid phosphatase). Studies to test these potential virulence mechanisms can be accelerated with the recent development of the complete genome sequence for the prototype acute disease isolate, Nine Mile. Proteins differentially expressed during the developmental cycle can more readily be identified with MALDI-TOF description of proteomic profiles. Genes encoding secreted Cu/Zn SOD, catalase, and acid phosphatase are predicted and can be tested for function and expression. An iron regulon is predicted based upon Fur-regulated open reading frames. The specific role the iron-regulated genes play in iron acquisition can be tested. Confirmation of the iron regulon and others can be tested using microarrays based upon the genomic ORF predictions. These are examples of how we are rapidly changing the experimental approaches used to investigate C. burnetii to improve our understanding of the biology of this unusual and highly adapted organism.