Scientists decipher genetic code of biothreat pathogen

Highly regulated virulence genes and genomic instability found in the horse pathogen, burkholderia mallei

More than 2,400 years after Hippocrates first described the symptoms of glanders, scientists have deciphered the genetic code of the ancient pathogen that causes the horse disease: Burkholderia mallei.

The study found that B. mallei, a highly evolved pathogen that has been deployed in the past as a biological weapon, has an extremely regulated set of virulence genes and an unstable genome that may explain the bacterium’s ability to thwart the immune responses of its host animals – mainly horses, mules and donkeys. “The combination of virulence genes and genomic instability may explain why some scientists consider this to be the ultimate bacterial pathogen,” says William Nierman, the first author of the study, which is being published in the Proceedings of the National Academy of Sciences (PNAS).

As part of the study, scientists used DNA microarrays to better understand the functions of B. mallei virulence genes. Nierman, an investigator at The Institute for Genomic Research (TIGR), said the new study, along with a report on the related bacterium B. pseudomallei published in the same issue of PNAS, “has dramatically increased our understanding of the biology and pathogenicity of these very sophisticated pathogens.”

Even though the symptoms of glanders have been known since the description by Hippocrates in 425 B.C., scientists have yet to develop a vaccine that is effective against this highly infectious equine disease. When humans are infected, treatment requires a long-term regimen of multiple antibiotics. A test developed by German scientists after B. mallei was isolated in 1882 greatly improved the early detection of the disease in horses. Glanders was eradicated in the United States by the 1930s.

Cultures of B. mallei were used as biological weapons during the U.S. Civil War, World War I and World War II. In addition, there have been reports that the Soviet Union weaponized the pathogen and possibly used it during the Soviet occupation of Afghanistan.

TIGR collaborated on the B. mallei study with a research team led by David DeShazer, a glanders expert with the U.S. Army Medical Research Institute for Infectious Diseases (USAMRIID) in Frederick, MD. The parallel study of B. pseudomallei, which causes the disease melioidosis in humans, was conducted by a team led by scientists at the Wellcome Trust Sanger Institute in the United Kingdom.

The B. mallei study was funded by the National Institute of Allergy and Infectious Diseases (NIAID), which is part of the National Institutes of Health. Following up the genome analysis, TIGR is now examining several other strains and isolates of B. mallei and B. pseudomallei under an NIAID microbial sequencing contract. “Using the tools of comparative genomics, scientists will be able to deepen the understanding of the molecular reasons why these related pathogens have such different impacts, in terms of their target hosts and their pathogenicity,” says TIGR President Claire Fraser, the study’s senior author.