title: Genomic characterization of Burkholderia pseudomallei isolates selected for medical countermeasures testing: comparative genomics associated with differential virulence.
abstract: Burkholderia pseudomallei is the causative agent of melioidosis and a potential bioterrorism agent. In the development of medical countermeasures against B. pseudomallei infection, the US Food and Drug Administration (FDA) animal Rule recommends using well-characterized strains in animal challenge studies. In this study, whole genome sequence data were generated for 6 B. pseudomallei isolates previously identified as candidates for animal challenge studies; an additional 5 isolates were sequenced that were associated with human inhalational melioidosis. A core genome single nucleotide polymorphism (SNP) phylogeny inferred from a concatenated SNP alignment from the 11 isolates sequenced in this study and a diverse global collection of isolates demonstrated the diversity of the proposed Animal Rule isolates. To understand the genomic composition of each isolate, a large-scale blast score ratio (LS-BSR) analysis was performed on the entire pan-genome; this demonstrated the variable composition of genes across the panel and also helped to identify genes unique to individual isolates. In addition, a set of ~550 genes associated with pathogenesis in B. pseudomallei were screened against the 11 sequenced genomes with LS-BSR. Differential gene distribution for 54 virulence-associated genes was observed between genomes and three of these genes were correlated with differential virulence observed in animal challenge studies using BALB/c mice. Differentially conserved genes and SNPs associated with disease severity were identified and could be the basis for future studies investigating the pathogenesis of B. pseudomallei. Overall, the genetic characterization of the 11 proposed Animal Rule isolates provides context for future studies involving B. pseudomallei pathogenesis, differential virulence, and efficacy to therapeutics.
authors: Department of Pathogen Genomics, Translational Genomics Research Institute, Flagstaff, Arizona, United States of America; Center for Microbial Genetics and Genomics, Northern Arizona University, Flagstaff, Arizona, United States of America.
authors: Jason W
authors: JW
authors: Sahl
authors: Center for Microbial Genetics and Genomics, Northern Arizona University, Flagstaff, Arizona, United States of America.
authors: Christopher J
authors: CJ
authors: Allender
authors: Department of Pathogen Genomics, Translational Genomics Research Institute, Flagstaff, Arizona, United States of America.
authors: Rebecca E
authors: RE
authors: Colman
authors: Center for Microbial Genetics and Genomics, Northern Arizona University, Flagstaff, Arizona, United States of America.
authors: Katy J
authors: KJ
authors: Califf
authors: Department of Pathogen Genomics, Translational Genomics Research Institute, Flagstaff, Arizona, United States of America.
authors: James M
authors: JM
authors: Schupp
authors: Department of Tropical and Emerging Infectious Diseases, Menzies School of Health Research, Casuarina NT, Australia.
authors: Bart J
authors: BJ
authors: Currie
authors: Battelle Biomedical Research Center (BBRC), Columbus, Ohio, United States of America.
authors: Kristopher E
authors: KE
authors: Van Zandt
authors: Battelle Biomedical Research Center (BBRC), Columbus, Ohio, United States of America.
authors: H Carl
authors: HC
authors: Gelhaus
authors: Department of Pathogen Genomics, Translational Genomics Research Institute, Flagstaff, Arizona, United States of America; Center for Microbial Genetics and Genomics, Northern Arizona University, Flagstaff, Arizona, United States of America.
authors: Paul
authors: P
authors: Keim
authors: Department of Tropical Medicine, Medical Microbiology and Pharmacology, and Pacific Center for Emerging Infections Diseases Research, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America.
authors: Apichai
authors: A
authors: Tuanyok
mesh_terms: D000818:Animals; D016957:Burkholderia pseudomallei / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification / Q000472:pathogenicity*; D055808:Drug Discovery; D019143:Evolution, Molecular; D005260:Female; D016680:Genome, Bacterial / Q000235:genetics; D023281:Genomics; D005838:Genotype; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D014774:Virulence / Q000187:drug effects / Q000235:genetics