Burkholderia mallei, one of the organisms used by the Soviets in their bioweapons program, possesses properties that contribute to its potential as a biological weapon. The disease, glanders, can result from an extremely low infectious dose inoculated by either aerosol, oral, or parental routes. The incubation period is short and no effective vaccine is available. Although glanders is a serious life-threatening zoonotic disease, relatively little is known about the pathogenesis, virulence factors, strain differences, and the host immunopathologic responses to infection. The sequencing of the complete genome of this organism is now underway at The Institute For Genome Research (TIGR). This proposal will constitute an initial effort to use the genome sequence of the organism in studies of its pathogenicity. A whole genome glass slide microarray will be constructed from PCR products representing each ORF in the genome. This microarray will be used in a series of experiments to explore the genetic response of this organism to infection of a model animal, the Syrian hamster. Comparative genome hybridization will be conducted with genomic DNA from a closely related non- pathogenic Burkholderia strain, Burkholderia thailandensis, using the microarray to further identify candidate virulence determinants. Genes involved in the establishment of a successful infection and evasion of the host immune system will be identified as will vaccine and drug target candidates. Function and virulence validation of the identified virulence genes will be explored by construction and phenotype analysis of targeted knockout strains.
