Genetic Blueprint for Q Fever Bacterium Unveiled

WASHINGTON -- The genetic blueprint of yet another important disease-causing microbe, the bacterium Coxiella burnetii, has been deciphered and analyzed. C. burnetii - a highly infectious organism that sickened thousands of soldiers in Europe during World War II - can cause a debilitating flu-like illness in humans called Q fever. Additionally, the microbe is a potential agent of bioterrorism. Although only severe cases of Q fever are fatal, C. burnetii is of concern as a potential bioterrorist threat because early diagnosis of the disease is difficult, and the microbe is a hardy organism that can be aerosolized.

A report describing the sequencing project was published online the week of April 14, 2003 in The Proceedings of the National Academy of Sciences and will appear in the journal's April 29th print edition.

The research project, led by John Heidelberg, PhD, and Rekha Seshadri, PhD, at The Institute of Genomic Research in Rockville, MD, was supported by the National Institute of Allergy and Infectious Diseases (NIAID) and the Defense Advanced Research Projects Agency (DARPA). Study collaborators included Robert A. Heinzen, PhD, of NIAID's Rocky Mountain Laboratories in Hamilton, MT; Herbert A. Thompson, PhD, of the Centers for Disease Control and Prevention in Atlanta; and James E. Samuel, PhD, of Texas A&M University System Health Science Center in College Station. Of historical note, the Nine Mile strain of Coxiella burnetii just sequenced was discovered and isolated by Harold Cox, PhD, and his colleague Gordon Davis, PhD, in the mid-1930s while working at Rocky Mountain Laboratories.

"The genomic revolution promises profound benefits to human health," says NIAID Director Anthony S. Fauci, MD. "Together with researchers around the world, NIAID continues to make significant contributions to a true revolution in biomedical research: the use of microbial genomic information to illuminate disease pathogenesis and to find new targets for drugs, vaccines and diagnostics." In recent years, NIAID has supported the completed sequencing efforts for approximately 30 medically important microbes, many of which are causative agents of emerging infectious diseases or potential agents of bioterrorism (see http://www.niaid.nih.gov/dmid/genomes).

"This genome sequence offers a treasure trove of information that will allow scientists to develop a much higher-resolution picture of Coxiella's biology and its ability to cause disease," notes Heidelberg, who supervised the latest project.

C. burnetii is difficult to manipulate genetically because it only replicates inside mammalian cells. It primarily resides in human immune cells called macrophages, known as indiscriminate microbe-eaters. C. burnetii is unusual because it has an uncanny ability to survive in the environment and resist being degraded by macrophages.

"The Coxiella genome sequence is a major advance," adds Heinzen. "Not only will it allow us to more easily study genes that may be involved in causing disease, it also should reveal targets for improved diagnostics and potential vaccine candidates." The analysis found many genes that appear to be involved in the microbe's virulence and interactions with its human or animal host. Although the organism does not cause obvious disease in most animals, infected livestock are the primary reservoir of the bacterium.

Heinzen, who has studied C. burnetii and related bacteria for about 20 years, helped the project leaders at TIGR interpret what the genome revealed about the biology of the organism. Among the team's findings, the Q fever microbe does not appear to be as dependent on its human or animal host as other intracellular pathogens that cause leprosy, typhus fever or chlamydial infection, for example, indicating that C. burnetii developed the intracellular adaptation more recently. The Q fever genome also appears to be less stable than the genomes of these pathogens.

NIAID recently published its roadmap for biodefense research priorities on category B and C pathogens, including C. burnetii (see http://biodefense.niaid.nih.gov/biodefense/research/strat_plan.htm). Currently, Heinzen notes, the number of researchers studying the Q fever agent is small. He thinks there will be a "renaissance" in C. burnetii research because of new interest in it as a select agent and because of the just reported genomic data and analysis, which makes the organism much more amenable to study. One research focus in his laboratory is how the microbe persists within the toxic environment of the macrophage. Already, James M. Musser, PhD, and Stephen Porcella, PhD, colleagues of Heinzen at NIAID's Rocky Mountain Laboratories, have added the Coxiella genome to a recently constructed multi-pathogen microarray gene chip they constructed. The chip will facilitate research on the Q fever bug.

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Reference: R Seshadri et al. Complete genome sequence of the Q-fever pathogen, Coxiella burnetii. Proceedings of the National Academy of Sciences Online Early Edition the week of April 14, 2003. DOI 10.1073/pnas.0931379100.