"Q Fever" Pathogen's Genome Is Deciphered

Small Genome Variations Account For Wide Range of Diseases, Victims

April 14, 2003

Rockville, MD -- Scientists at The Institute for Genomic Research (TIGR) and their collaborators have deciphered and analyzed the complete genome sequence of Coxiella burnetii, a potential bioterror agent that causes Q Fever.

C. burnetii, which was first isolated as the cause of Q Fever in Australia in 1937, is typically found in farm animals but also infects humans, including an epidemic that sickened many soldiers in Europe during World War II. Typically, Q Fever does not kill people, but causes fever and other flu-like symptoms.

Because C. burnetii is an obligate intracellular pathogen - unable to replicate unless it is inside the cells of another living organism -- it is difficult to study in laboratories. That makes the complete DNA sequence an extremely valuable resource for researchers.

"The 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," says John F. Heidelberg, the TIGR scientist who supervised the project.

The paper will be published online this week by the Proceedings of the National Academy of Sciences (PNAS), and will appear in the journal's April 29 issue. The sequencing project was supported by the Defense Advanced Research Projects Agency (DARPA) and the National Institute of Allergy and Infectious Diseases (NIAID).

The TIGR study found that the C. burnetii genome appears to be in the early stages of "reduction" - a process during which degraded or non-functional genes are slowly eliminated as the organism becomes more dependent on its host for nutrition. Even so, scientists say, the Q Fever microbe does not appear to be quite as dependent on its human or animal host as other intracellular pathogens that cause leprosy, chlamydia, typhus, and Legionnaire's Disease.

"This may mean that Coxiella became an intracellular pathogen more recently than other, somewhat similar pathogens," says Rekha Seshadri, the TIGR staff scientist who is the lead author of the PNAS paper. "Comparing Coxiella with the genomes of other intracellular pathogens reveals fundamental differences in the organization and evolution of their chromosomes, as well as in their strategies for surviving inside host cells."

The analysis found numerous genes that appear to be involved in the pathogen's virulence and interactions with its host. In addition, Seshadri says, researchers found that the C. burnetii genome - which includes multiple "mobile elements" of DNA - seems to be less stable than that of other obligate intracellular pathogens such as Rickettsia and Chlamydia. The evidence of mobile elements and gene degradation suggests greater genome flux.

The study was led by TIGR researchers in collaboration with other scientists, including James E. Samuel of the Department of Medical Microbiology and Immunology at Texas A&M University System Health Science Center, in College Station, TX; Herbert A. Thompson of the Centers for Disease Control and Prevention (CDC) in Atlanta, GA; and Robert A. Heinzen of the NIAID's Rocky Mountain Laboratories in Hamilton, MT.

"The availability of the genome sequence for Coxiella burnetii will provide a quantum leap to the investigators engaged in understanding the biology of this pathogen," said Samuel of Texas A&M. "The most immediate application of the genome sequence will be testing of the predicted essential genes for Coxiella's survival."

Samuel said the genome sequence - coupled with NIAID's heightened emphasis on vaccine development for Q Fever and other Category B potential bioterror agents - is likely to accelerate the development of better vaccines and diagnostic tests using genomic and proteomic approaches.

The CDC's Thompson, co-editor of the book Q Fever: The Biology of Coxiella burnetii, says, "Q Fever research on all fronts will benefit from this new knowledge." Over the last several years, he says, "consideration for both the organism Coxiella and its disease manifestations have been neglected" - mainly because of the difficulties involved with studying and manipulating the organism in the lab. "Knowledge of the genome should significantly aid our inquiries and guide us as we attempt to remedy these shortcomings."

Heinzen, of NIAID's Rocky Mountain Laboratory, says that having Coxiella's complete genome sequence "is a major advance that will allow scientists to more easily conduct functional studies of genes potentially involved in virulence." He said the pathogen interests scientists because it has "an amazing ability to survive in the environment and to resist degradation by its macrophage host cell."

TIGR, which in 1995 published the first complete genome sequence of a free-living organism, is a world leader in microbial genomics. The institute has completed the full sequences of about 50 organisms or microbial strains - including the potential bioterror agents Bacillus anthracis and Brucella suis - and is now working on numerous other sequencing projects.

C. burnetii is listed as a potential bioweapon/bioterror agent because it is highly infective, relatively stable, and because Q Fever's flu-like disease symptoms make early diagnosis difficult. During the 1950s and 1960s, the U.S. military required conducted research into the potential use of C. burnetii as a biowarfare agent. But that stockpile was destroyed after the U.S. government halted its biowarfare development program in 1969. The former Soviet Union also conducted Q Fever bioweapons research during the Cold War.