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Genomic Plasticity of the Causative Agent of Melioidosis, Burkholderia Pseudomallei

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Genomic Plasticity of the Causative Agent of Melioidosis, Burkholderia Pseudomallei Genomic plasticity of the causative agent of melioidosis, Burkholderia pseudomallei Matthew T. G. Holdena, Richard W. Titballb,c, Sharon J. Peacockd,e, Ana M. Cerden˜ o-Ta´ rragaa, Timothy Atkinsb, Lisa C. Crossmana, Tyrone Pittf, Carol Churchera, Karen Mungalla, Stephen D. Bentleya, Mohammed Sebaihiaa, Nicholas R. Thomsona, Nathalie Basona, Ifor R. Beachamg, Karen Brooksa, Katherine A. Brownh, Nat F. Browng, Greg L. Challisi, Inna Cherevacha, Tracy Chillingwortha, Ann Cronina, Ben Crossetth, Paul Davisa, David DeShazerj, Theresa Feltwella, Audrey Frasera, Zahra Hancea, Heidi Hausera, Simon Holroyda, Kay Jagelsa, Karen E. Keithh, Mark Maddisona, Sharon Moulea, Claire Pricea, Michael A. Quaila, Ester Rabbinowitscha, Kim Rutherforda, Mandy Sandersa, Mark Simmondsa, Sirirurg Songsivilaik, Kim Stevensa, Sarinna Tumapae, Monkgol Vesaratchaveste, Sally Whiteheada, Corin Yeatsa, Bart G. Barrella, Petra C. F. Oystonb, and Julian Parkhilla,l aWellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom; bDefence Science and Technology Laboratory, Porton Down, Salisbury SP4 0JQ, United Kingdom; cDepartment of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom; dNuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, United Kingdom; eFaculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand; fLaboratory of Hospital Infection, Division of Nosocomial Infection Prevention and Control, Central Public Health Laboratory, London NW9 5HT, United Kingdom; gSchool of Health Science, Griffith University, Gold Coast, Queensland 9726, Australia; hDepartment of Biological Sciences, Centre for Molecular Microbiology and Infection, Flowers Building, Imperial College, London SW7 2AZ, United Kingdom; iDepartment of Chemistry, University of Warwick, Coventry CV4 7AL, United Kingdom; jU.S. Army Medical Research Institute for Infectious Diseases, 1425 Porter Street, Fort Detrick, MD 21702-5011; and kDepartment of Immunology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand Edited by E. Peter Greenberg, University of Iowa, Iowa City, IA, and approved August 13, 2004 (received for review May 10, 2004) Burkholderia pseudomallei is a recognized biothreat agent and the clinical manifestations are protean and have led to the infec- causative agent of melioidosis. This Gram-negative bacterium tion being termed ‘‘the great mimicker’’ (6). Of the cases in exists as a soil saprophyte in melioidosis-endemic areas of the Thailand, one-fifth occur in children under the age of 14 years, world and accounts for 20% of community-acquired septicaemias for whom the overall mortality of infected individuals is 51% in northeastern Thailand where half of those affected die. Here we (3). Death usually occurs within the first 48 h as a result of report the complete genome of B. pseudomallei, which is com- septic shock and in a setting where optimal antimicrobial posed of two chromosomes of 4.07 megabase pairs and 3.17 chemotherapy is given. Of equal concern, there is evidence megabase pairs, showing significant functional partitioning of that the bacterium does not cause overt disease in all individ- genes between them. The large chromosome encodes many of the uals exposed to the bacterium but is able to persist at unknown core functions associated with central metabolism and cell growth, sites in the body to become reactivated later in life. Possibly the whereas the small chromosome carries more accessory functions best documented examples of this are in Vietnam veterans who associated with adaptation and survival in different niches. developed disease, in one case 26 years later, after returning Genomic comparisons with closely and more distantly related to the U.S. (7–9). bacteria revealed a greater level of gene order conservation and a Here we describe the 7.25-megabase pair (Mb) genome of B. greater number of orthologous genes on the large chromosome, pseudomallei strain K96243, isolated from a case of human suggesting that the two replicons have distinct evolutionary ori- melioidosis. Comparative analysis highlights the role that gins. A striking feature of the genome was the presence of 16 horizontal gene acquisition has played in the evolution of the genomic islands (GIs) that together made up 6.1% of the genome. genome and clarifies the genetic relationship of B. pseudoma- Further analysis revealed these islands to be variably present in a llei with Burkholderia mallei, the genome of which is described collection of invasive and soil isolates but entirely absent from the in an accompanying manuscript (10). The work presented here clonally related organism B. mallei. We propose that variable also provides insights into the molecular basis of environmen- horizontal gene acquisition by B. pseudomallei is an important tal survival, virulence, and antimicrobial resistance. feature of recent genetic evolution and that this has resulted in a genetically diverse pathogenic species. Materials and Methods Bacterial Strain, Growth, and DNA Isolation. B. pseudomallei strain elioidosis is a bacterial infection caused by Burkholderia K96243 was isolated in 1996 from a 34-year-old female diabetic Mpseudomallei, an environmental Gram-negative sapro- patient in Khon Kaen hospital in Thailand. K96243 is sensitive phyte present in wet soil and rice paddies in endemic areas to imipenem, ceftazidime, chloramphenicol, ciprofloxacin, (1–3). The majority of infections are reported from east Asia and augmentin and resistant to minocycline, gentamicin, co- and northern Australia, the highest documented rate being in trimoxazole, and streptomycin. The API 20NE profile of the northeastern Thailand, where melioidosis accounts for 20% of bacterium was 1156576. The median lethal dose in Porton all community-acquired septicaemias (4). Disease occurs after strain mice by the intraperitoneal route was 262 colony- bacterial contamination of breaks in the skin or by inhalation forming units. Bacteria were cultured in L broth at 37°C for after contact with water or soil. A pneumonic form of the disease can also result from the inhalation of contaminated dusts and was reported in U.S. helicopter pilots during the This paper was submitted directly (Track II) to the PNAS office. Vietnam War. The potential for the bacterium to cause disease Freely available online through the PNAS open access option. after inhalation has also resulted in the inclusion of this Abbreviations: GI, genomic island; CDS, coding sequence; Mb, megabase pair; IS, insertion pathogen on the Centers for Disease Control list of potential sequence. biothreat agents as a Category B agent (5). The most frequent Data deposition: The sequences reported in this paper have been deposited in the Euro- clinical picture is a septicaemic illness associated with bacterial pean Molecular Biology Laboratory database (accession nos. BX571965 and BX571966). dissemination to distant sites, such that metastatic pneumonia lTo whom correspondence should be addressed. E-mail: [email protected]. and hepatic and splenic abcesses are common. However, © 2004 by The National Academy of Sciences of the USA 14240–14245 ͉ PNAS ͉ September 28, 2004 ͉ vol. 101 ͉ no. 39 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0403302101 Downloaded by guest on October 1, 2021 Fig. 1. Schematic circular diagrams of the large and small chromosomes of the B. pseudomallei genome. Where appropriate, categories are shown as pairs of concentric circles representing both coding strands. Rings from outside to inside: GIs represented by red segments; scale (in Mb); annotated CDSs colored according to predicted function; additional CDSs compared to the sequenced B. mallei strain ATCC 2944; the percentage of G ϩ C content plot; (G Ϫ C)͞(G ϩ C) deviation plot (Ͼ0%, olive; Ͻ0%, purple). Color coding for CDSs: dark blue, pathogenicity͞adaptation; black, energy metabolism; red, information transfer; dark green, surface-associated; cyan, degradation of large molecules; magenta, degradation of small molecules; yellow, central͞ intermediary metabolism; pale green, unknown; pale blue, regulators; orange, conserved hypothetical; brown, pseudogenes; pink, phage plus IS elements; gray, miscellaneous. 18 h and pelleted at 10,000 ϫ g. The cells were resuspended in DNA. Detailed information, including the primer sequences and 30 ml of lysis solution (10 mM NaCl͞20 mM Tris⅐HCl, pH 8.0͞1 PCR conditions, is available in Supporting Text. MICROBIOLOGY mM EDTA͞0.5% SDS) and incubated at 50°C overnight. Three milliliters of 5 M sodium perchlorate was added and Results and Discussion incubated for1hatambient temperature. After phenol The complete genome of B. pseudomallei strain K96243 con- chloroform extraction, the DNA was precipitated with etha- sists of two circular replicons (European Molecular Biology nol, spooled into deionized water, and stored at Ϫ20°C. Laboratory accession nos. BX571965 and BX571966) of 4.07 Mb and 3.17 Mb (Fig. 1) each that have been designated Whole-Genome Sequencing. The sequence was assembled, fin- chromosome 1 and chromosome 2 and encode 3,460 and 2,395 ished, and annotated as described in ref. 11 by using ARTEMIS to coding sequences (CDSs), respectively (for a summary of the collate data and facilitate annotation (12); detailed information features of the chromosomes, see Table 7, which is published is available in Supporting Text and Tables 3–6, which are as supporting information on
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