Publications

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a sensitive & specific multiplex pcr assay for simultaneous detection of bacillus anthracis, yersinia pestis, burkholderia pseudomallei & brucella species.bacillus anthracis, yersinia pestis, burkholderia pseudomallei and brucella species are potential biowarfare agents. classical bacteriological methods for their identification are cumbersome, time consuming and of potential risk to the handler.201324056564
the in vivo extracellular life of facultative intracellular bacterial parasites: role in pathogenesis.classically labeled facultative intracellular pathogens are characterized by the ability to have an intracellular phase in the host, which is required for pathogenicity, while capable of extracellular growth in vitro. the ability of these bacteria to replicate in cell-free conditions is usually assessed by culture in artificial bacteriological media. however, the extracellular growth ability of these pathogens may also be expressed by a phase of extracellular infection in the natural setting of ...201322795971
rapid detection of burkholderia pseudomallei in blood cultures using a monoclonal antibody-based immunofluorescent assay.melioidosis is a severe bacterial infection caused by burkholderia pseudomallei. rapid antimicrobial therapy is necessary to improve patient outcome, which is aided by direct detection of b. pseudomallei in clinical samples. a drawback for all antigen assays is that the number of b. pseudomallei in blood usually falls below the achievable level of detection. we performed a prospective cohort study of 461 patients with 541 blood cultures to evaluate the utility of a pre-incubation step prior to d ...201324019434
human melioidosis, malawi, 2011.a case of human melioidosis caused by a novel sequence type of burkholderia pseudomallei occurred in a child in malawi, southern africa. a literature review showed that human cases reported from the continent have been increasing.201323735189
structural insights into wcbi, a novel polysaccharide-biosynthesis enzyme.capsular polysaccharides (cpss) are protective structures on the surfaces of many gram-negative bacteria. the principal cps of the human pathogen and tier 1 select agent burkholderia pseudomallei consists of a linear repeat of --3)--2-o-acetyl-6-deoxy-β-d-manno-heptopyranose-(1-. this cps is critical to the virulence of this emerging pathogen and represents a key target for the development of novel therapeutics. wcbi is one of several genes in the cps biosynthetic cluster whose deletion leads to ...201325075317
an improved method for orit-directed cloning and functionalization of large bacterial genomic regions.we have made significant improvements to a broad-host-range system for the cloning and manipulation of large bacterial genomic regions based on site-specific recombination between directly repeated orit sites during conjugation. using two suicide capture vectors carrying flanking homology regions, orit sites are recombined on either side of the target region. using a broad-host-range conjugation helper plasmid, the region between the orit sites is conjugated into an escherichia coli recipient st ...201323747708
functional characterization of burkholderia pseudomallei trimeric autotransporters.burkholderia pseudomallei is a tier 1 select agent and the causative agent of melioidosis, a severe and often fatal disease with symptoms ranging from acute pneumonia and septic shock to a chronic infection characterized by abscess formation in the lungs, liver, and spleen. autotransporters (ats) are exoproteins belonging to the type v secretion system family, with many playing roles in pathogenesis. the genome of b. pseudomallei strain 1026b encodes nine putative trimeric at proteins, of which ...201323716608
melioidosis from contaminated bore water and successful uv sterilization.two cases of melioidosis at a residence in rural northern australia were linked to the unchlorinated domestic bore (automated well) water supply, which was found to have a high concentration of burkholderia pseudomallei. using multilocus sequence typing, clinical b. pseudomallei isolates from both cases were identical to an isolate from the bore water supply. a simple uv sterilizer reduced b. pseudomallei from the domestic water supply to undetectable levels. we have shown that uv treatment is h ...201323751401
impaired tlr5 functionality is associated with survival in melioidosis.melioidosis is infection caused by the flagellated saprophyte burkholderia pseudomallei. tlr5 is a pathogen recognition receptor activated by bacterial flagellin. we studied a genetic variant that encodes a defective tlr5 protein, tlr5(1174c)>t, to elucidate the role of tlr5 in melioidosis. we measured nf-κb activation induced by b. pseudomallei in human embryonic kidney-293 cells transfected with tlr5 and found that b. pseudomallei induced tlr5(1174c)- but not tlr5(1174t)-dependent activation o ...201323447684
polar lipids of burkholderia pseudomallei induce different host immune responses.melioidosis is a disease in tropical and subtropical regions of the world that is caused by burkholderia pseudomallei. in endemic regions the disease occurs primarily in humans and goats. in the present study, we used the goat as a model to dissect the polar lipids of b. pseudomallei to identify lipid molecules that could be used for adjuvants/vaccines or as diagnostic tools. we showed that the lipidome of b. pseudomallei and its fractions contain several polar lipids with the capacity to elicit ...201324260378
evolutionary analysis of burkholderia pseudomallei identifies putative novel virulence genes, including a microbial regulator of host cell autophagy.burkholderia pseudomallei, the causative agent of melioidosis, contains a large pathogen genome (7.2 mb) with ∼2,000 genes of putative or unknown function. interactions with potential hosts and environmental factors may induce rapid adaptations in these b. pseudomallei genes, which can be discerned through evolutionary analysis of multiple b. pseudomallei genomes. here we show that several previously uncharacterized b. pseudomallei genes bearing genetic signatures of rapid adaptation (positive s ...201324097950
multiple-antigen elisa for melioidosis--a novel approach to the improved serodiagnosis of melioidosis.burkholderia pseudomallei, the causative agent of melioidosis, is endemic to southeast asia and northern australia. clinical manifestations of disease are diverse, ranging from chronic infection to acute septicaemia. the current gold standard of diagnosis involves bacterial culture and identification which is time consuming and often too late for early medical intervention. hence, rapid diagnosis of melioidosis is crucial for the successful management of melioidosis.201323556548
epidemiology of bacteremia caused by uncommon non-fermentative gram-negative bacteria.prevalence of bacteremia caused by non-fermentative gram-negative bacteria (nfgnb) has been increasing over the past decade. although many studies have already investigated epidemiology of nfgnb bacteremia, most focused only on common nfgnb including pseudomonas aeruginosa (pa) and acinetobacter baumannii (ab). knowledge of uncommon nfgnb bacteremia is very limited. our study aimed to investigate epidemiology and identify factors associated with uncommon nfgnb bacteremia.201323566113
a prospective study of the causes of febrile illness requiring hospitalization in children in cambodia.febrile illnesses are pre-eminent contributors to morbidity and mortality among children in south-east asia but the causes are poorly understood. we determined the causes of fever in children hospitalised in siem reap province, cambodia.201323593267
melioidosis in traveler from africa to spain.the worldwide epidemiology of melioidosis is changing. we describe a case of acute melioidosis in spain in a patient who had traveled to africa. a novel sequence type of burkholderia pseudomallei was identified in this patient. clinicians should be aware of the possibility of melioidosis in travelers returning from melioidosis-nonendemic regions.201324047798
reliability of automated biochemical identification of burkholderia pseudomallei is regionally dependent.misidentifications of burkholderia pseudomallei as burkholderia cepacia by vitek 2 have occurred. multidimensional scaling ordination of biochemical profiles of 217 malaysian and australian b. pseudomallei isolates found clustering of misidentified b. pseudomallei isolates from malaysian borneo. specificity of b. pseudomallei identification in vitek 2 and potentially other automated identification systems is regionally dependent.201323784129
genomic characterization of jg068, a novel virulent podovirus active against burkholderia cenocepacia.as is true for many other antibiotic-resistant gram-negative pathogens, members of the burkholderia cepacia complex (bcc) are currently being assessed for their susceptibility to phage therapy as an antimicrobial treatment. the objective of this study was to perform genomic and limited functional characterization of the novel bcc phage jg068 (vb_bcep_jg068).201323978260
accurate and rapid identification of the burkholderia pseudomallei near-neighbour, burkholderia ubonensis, using real-time pcr.burkholderia ubonensis is an environmental bacterium belonging to the burkholderia cepacia complex (bcc), a group of genetically related organisms that are associated with opportunistic but generally nonfatal infections in healthy individuals. in contrast, the near-neighbour species burkholderia pseudomallei causes melioidosis, a disease that can be fatal in up to 95% of cases if left untreated. b. ubonensis is frequently misidentified as b. pseudomallei from soil samples using selective culturi ...201323967229
monoclonal antibody-based immunofluorescence microscopy for the rapid identification of burkholderia pseudomallei in clinical specimens.the diagnosis of melioidosis depends on the culture of burkholderia pseudomallei, which takes at least 48 hours. we used a polyclonal-fitc-based immunofluorescence microscopic assay (pab-ifa) on clinical samples to provide a rapid presumptive diagnosis. this has limitations including photobleaching and batch-to-batch variability. this study evaluated an ifa based on a monoclonal antibody specific to b. pseudomallei (mab-ifa) and alexa fluor 488. a diagnostic evaluation was performed on a prospec ...201323716405
antibacterial activity of a lectin-like burkholderia cenocepacia protein.bacteriocins of the llpa family have previously been characterized in the γ-proteobacteria pseudomonas and xanthomonas. these proteins are composed of two mmbl (monocot mannose-binding lectin) domains, a module predominantly and abundantly found in lectins from monocot plants. genes encoding four different types of llpa-like proteins were identified in genomes from strains belonging to the burkholderia cepacia complex (bcc) and the burkholderia pseudomallei group. a selected recombinant llpa-lik ...201323737242
insights into β-lactamases from burkholderia species, two phylogenetically related yet distinct resistance determinants.burkholderia cepacia complex and burkholderia pseudomallei are opportunistic human pathogens. resistance to β-lactams among burkholderia spp. is attributable to expression of β-lactamases (e.g. pena in b. cepacia complex and peni in b. pseudomallei). phylogenetic comparisons reveal that pena and peni are highly related. however, the analyses presented here reveal that pena is an inhibitor-resistant carbapenemase, most similar to kpc-2 (the most clinically significant serine carbapenemase), where ...201323658015
comparison of dna extraction kits for detection of burkholderia pseudomallei in spiked human whole blood using real-time pcr.burkholderia pseudomallei, the etiologic agent of melioidosis, is endemic in northern australia and southeast asia and can cause severe septicemia that may lead to death in 20% to 50% of cases. rapid detection of b. pseudomallei infection is crucial for timely treatment of septic patients. this study evaluated seven commercially available dna extraction kits to determine the relative recovery of b. pseudomallei dna from spiked edta-containing human whole blood. the evaluation included three manu ...201323460920
in vivo manipulation of γ9(+) t cells in the common marmoset (callithrix jacchus) with phosphoantigen and effect on the progression of respiratory melioidosis.burkholderia pseudomallei is a dangerous human pathogen. phosphoantigens specifically the target primate specific γ9(+)δ2(+) t cells subset and some have been developed as potential immunotherapeutics. previously, we demonstrated that, when stimulated with the phosphoantigen chdmapp, γ9(+)δ2(+) t cells aid in the killing of intracellular b. pseudomallei bacteria. moreover, we found that common marmoset (callithrix jacchus) γ9(+) t cells increase in frequency and respond to the phosphoantigen chd ...201324098670
protection against experimental melioidosis following immunization with live burkholderia thailandensis expressing a manno-heptose capsule.melioidosis is a severe infectious disease caused by burkholderia pseudomallei. it is highly resistant to antibiotic treatment, and there is currently no licensed vaccine. burkholderia thailandensis is a close relative of burkholderia pseudomallei but is essentially avirulent in mammals. in this report, we detail the protective efficacy of immunization with live b. thailandensis e555, a strain which has been shown to express an antigenic capsule similar to that of b. pseudomallei. immunization w ...201323677322
importance of using bruker's security-relevant library for biotyper identification of burkholderia pseudomallei, brucella species, and francisella tularensis. 201323447635
development of burkholderia mallei and pseudomallei vaccines.burkholderia mallei and burkholderia pseudomallei are gram-negative bacteria that cause glanders and melioidosis, respectively. inhalational infection with either organism can result in severe and rapidly fatal pneumonia. inoculation by the oral and cutaneous routes can also produce infection. chronic infection may develop after recovery from acute infection with both agents, and control of infection with antibiotics requires prolonged treatment. symptoms for both meliodosis and glanders are non ...201323508691
multiplex qpcr for reliable detection and differentiation of burkholderia mallei and burkholderia pseudomallei.burkholderia mallei and b. pseudomallei are two closely related species of highly virulent bacteria that can be difficult to detect. pathogenic burkholderia are endemic in many regions worldwide and cases of infection, sometimes brought by travelers from unsuspected regions, also occur elsewhere. rapid, sensitive methods for identification of b. mallei and b. pseudomallei are urgently needed in the interests of patient treatment and epidemiological surveillance.201323409683
burkholderia vaccines: are we moving forward?the genus burkholderia consists of diverse species which includes both "friends" and "foes." some of the "friendly" burkholderia spp. are extensively used in the biotechnological and agricultural industry for bioremediation and biocontrol. however, several members of the genus including b. pseudomallei, b. mallei, and b. cepacia, are known to cause fatal disease in both humans and animals. b. pseudomallei and b. mallei are the causative agents of melioidosis and glanders, respectively, while b. ...201323386999
comparative experimental subcutaneous glanders and melioidosis in the common marmoset (callithrix jacchus).glanders and melioidosis are caused by two distinct burkholderia species and have generally been considered to have similar disease progression. while both of these pathogens are hhs/cdc tier 1 agents, natural infection with both these pathogens is primarily through skin inoculation. the common marmoset (callithrix jacchus) was used to compare disease following experimental subcutaneous challenge. acute, lethal disease was observed in marmosets following challenge with between 26 and 1.2 × 10(8) ...201425477002
migration of dendritic cells facilitates systemic dissemination of burkholderia pseudomallei.burkholderia pseudomallei, the etiological agent for melioidosis, is an important cause of community-acquired sepsis in northern australia and northeast thailand. due to the rapid dissemination of disease in acute melioidosis, we hypothesized that dendritic cells (dc) could act as a vehicle for dissemination of b. pseudomallei. therefore, this study investigated the effect of b. pseudomallei infection on dc migration capacity and whether migration of dc enabled transportation of b. pseudomallei ...201425069976
molecular characterization of putative virulence determinants in burkholderia pseudomallei.the gram-negative saprophyte burkholderia pseudomallei is the causative agent of melioidosis, an infectious disease which is endemic in southeast asia and northern australia. this bacterium possesses many virulence factors which are thought to contribute to its survival and pathogenicity. using a virulent clinical isolate of b. pseudomallei and an attenuated strain of the same b. pseudomallei isolate, 6 genes bpsl2033, bp1026b_i2784, bp1026b_i2780, burps1106a_a0094, burps1106a_1131, and burps171 ...201425215325
caspase-1-dependent and -independent cell death pathways in burkholderia pseudomallei infection of macrophages.the cytosolic pathogen burkholderia pseudomallei and causative agent of melioidosis has been shown to regulate il-1β and il-18 production through nod-like receptor nlrp3 and pyroptosis via nlrc4. downstream signalling pathways of those receptors and other cell death mechanisms induced during b. pseudomallei infection have not been addressed so far in detail. furthermore, the role of b. pseudomallei factors in inflammasome activation is still ill defined. in the present study we show that caspase ...201424626296
a structural biology approach enables the development of antimicrobials targeting bacterial immunophilins.macrophage infectivity potentiators (mips) are immunophilin proteins and essential virulence factors for a range of pathogenic organisms. we applied a structural biology approach to characterize a mip from burkholderia pseudomallei (bpml1), the causative agent of melioidosis. crystal structure and nuclear magnetic resonance analyses of bpml1 in complex with known macrocyclics and other derivatives led to the identification of a key chemical scaffold. this scaffold possesses inhibitory potency fo ...201424366729
substituted diphenyl ethers as a novel chemotherapeutic platform against burkholderia pseudomallei.identification of a novel class of anti-burkholderia compounds is key in addressing antimicrobial resistance to current therapies as well as naturally occurring resistance. the fabi enoyl-acp reductase in burkholderia is an underexploited target that presents an opportunity for development of a new class of inhibitors. a library of substituted diphenyl ethers was used to identify fabi1-specific inhibitors for assessment in burkholderia pseudomallei ex vivo and murine efficacy models. active fabi ...201424379198
efficient inactivation of burkholderia pseudomallei or francisella tularensis in infected cells for safe removal from biosafety level 3 containment laboratories.working with infectious agents that require bsl-3 level containment agents offers many challenges for researchers. bsl-3 containment laboratories are usually not equipped with expensive specialty equipment that is needed for studies such as flow cytometric analysis, microscopy, and proteomic analyses. therefore, for most researchers that are working with bsl-3 level infectious agents, removal of samples from bsl-3 laboratories for these types of studies is necessary, and methods for complete and ...201424449562
genome-wide saturation mutagenesis of burkholderia pseudomallei k96243 predicts essential genes and novel targets for antimicrobial development.burkholderia pseudomallei is the causative agent of melioidosis, an often fatal infectious disease for which there is no vaccine. b. pseudomallei is listed as a tier 1 select agent, and as current therapeutic options are limited due to its natural resistance to most antibiotics, the development of new antimicrobial therapies is imperative. to identify drug targets and better understand the complex b. pseudomallei genome, we sought a genome-wide approach to identify lethal gene targets. as b. pse ...201424520057
the burkholderia pseudomallei enoyl-acyl carrier protein reductase fabi1 is essential for in vivo growth and is the target of a novel chemotherapeutic with efficacy.the bacterial fatty acid biosynthesis pathway is a validated target for the development of novel chemotherapeutics. however, since burkholderia pseudomallei carries genes that encode both fabi and fabv enoyl-acyl carrier protein (acp) reductase homologues, the enoyl-acp reductase that is essential for in vivo growth needs to be defined so that the correct drug target can be chosen for development. accordingly, δfabi1, δfabi2, and δfabv knockout strains were constructed and tested in a mouse mode ...201424277048
molecular signatures and phylogenomic analysis of the genus burkholderia: proposal for division of this genus into the emended genus burkholderia containing pathogenic organisms and a new genus paraburkholderia gen. nov. harboring environmental species.the genus burkholderia contains large number of diverse species which include many clinically important organisms, phytopathogens, as well as environmental species. however, currently, there is a paucity of biochemical or molecular characteristics which can reliably distinguish different groups of burkholderia species. we report here the results of detailed phylogenetic and comparative genomic analyses of 45 sequenced species of the genus burkholderia. in phylogenetic trees based upon concatenat ...201425566316
the identification and differentiation between burkholderia mallei and burkholderia pseudomallei using one gene pyrosequencing.the etiologic agents for melioidosis and glanders, burkholderia mallei and burkholderia pseudomallei respectively, are genetically similar making identification and differentiation from other burkholderia species and each other challenging. we used pyrosequencing to determine the presence or absence of an insertion sequence is407a within the flagellin p (flip) gene and to exploit the difference in orientation of this gene in the two species. oligonucleotide primers were designed to selectively t ...201427350960
kdo hydroxylase is an inner core assembly enzyme in the ko-containing lipopolysaccharide biosynthesis.the lipopolysaccharide (lps) isolated from certain important gram-negative pathogens including a human pathogen yersinia pestis and opportunistic pathogens burkholderia mallei and burkholderia pseudomallei contains d-glycero-d-talo-oct-2-ulosonic acid (ko), an isosteric analog of 3-deoxy-d-manno-oct-2-ulosonic acid (kdo). kdo 3-hydroxylase (kdoo), a fe(2+)/α-kg/o2 dependent dioxygenase from burkholderia ambifaria and yersinia pestis is responsible for ko formation with kdo2-lipid a as a substrat ...201425204504
isolation, identification and characterization of burkholderia pseudomallei from soil of coastal region of india.melioidosis is an emerging infectious disease caused by a free living soil dwelling gram-negative bacterium burkholderia pseudomallei. the disease is endemic to most parts of southeast asia and northern australia and the organism has been isolated from moist soil and water. in india clinical cases are recently reported from the states of tamilnadu, kerala, karnataka, maharashtra, orissa, assam, west bengal, pondicherry and tripura. this study is aimed to confirm the prevalence of this important ...201425187882
the type vi secretion system spike protein vgrg5 mediates membrane fusion during intercellular spread by pseudomallei group burkholderia species.pseudomallei group burkholderia species are facultative intracellular parasites that spread efficiently from cell to cell by a mechanism involving the fusion of adjacent cell membranes. intercellular fusion requires the function of the cluster 5 type vi secretion system (t6ss-5) and its associated valine-glycine repeat protein, vgrg5. here we show that vgrg5 alleles are conserved and functionally interchangeable between burkholderia pseudomallei and its relatives b. mallei, b. oklahomensis, and ...201424421040
role of burkholderia pseudomallei biofilm formation and lipopolysaccharide in relapse of melioidosis.we examined whether quantitative biofilm formation and/or lipopolysaccharide type of burkholderia pseudomallei was associated with relapsing melioidosis. we devised a 1:4 nested case-control study in which both cases and controls were drawn from a cohort of patients with primary melioidosis. paired isolates from 80 patients with relapse and single isolates from 184 patients without relapse were tested. relapse was associated with biofilm formation of the primary infecting isolate (conditional or ...201424602145
functional characterization and evaluation of in vitro protective efficacy of murine monoclonal antibodies burk24 and burk37 against burkholderia pseudomallei.burkholderia pseudomallei, the causative agent of melioidosis has been recognized by cdc as a category b select agent. although substantial efforts have been made for development of vaccine molecules against the pathogen, significant hurdles still remain. with no licensed vaccines available and high relapse rate of the disease, there is a pressing need for development of alternate protection strategies. antibody-mediated passive protection is promising in this regard and our primary interest was ...201424614539
disarming burkholderia pseudomallei: structural and functional characterization of a disulfide oxidoreductase (dsba) required for virulence in vivo.the intracellular pathogen burkholderia pseudomallei causes the disease melioidosis, a major source of morbidity and mortality in southeast asia and northern australia. the need to develop novel antimicrobials is compounded by the absence of a licensed vaccine and the bacterium's resistance to multiple antibiotics. in a number of clinically relevant gram-negative pathogens, dsba is the primary disulfide oxidoreductase responsible for catalyzing the formation of disulfide bonds in secreted and me ...201423901809
the hica toxin from burkholderia pseudomallei has a role in persister cell formation.ta (toxin-antitoxin) systems are widely distributed amongst bacteria and are associated with the formation of antibiotic tolerant (persister) cells that may have involvement in chronic and recurrent disease. we show that overexpression of the burkholderia pseudomallei hica toxin causes growth arrest and increases the number of persister cells tolerant to ciprofloxacin or ceftazidime. furthermore, our data show that persistence towards ciprofloxacin or ceftazidime can be differentially modulated ...201424502667
evaluation of the remel rapid nf plus rapid biochemical method for identification of burkholderia pseudomallei.typical methods for the identification of burkholderia pseudomallei colonies produce results in 18 h. the remel rapid nf plus kit produces results in 4 h. we used the kit for 190 stored b. pseudomallei isolates and correctly identified 189 of them. this kit produces consistent results for known b. pseudomallei isolates.201424671779
the twin arginine translocation system is essential for aerobic growth and full virulence of burkholderia thailandensis.the twin arginine translocation (tat) system in bacteria is responsible for transporting folded proteins across the cytoplasmic membrane, and in some bacteria, tat-exported substrates have been linked to virulence. we report here that the tat machinery is present in burkholderia pseudomallei, b. mallei, and b. thailandensis, and we show that the system is essential for aerobic but not anaerobic growth. switching off of the tat system in b. thailandensis grown anaerobically resulted in filamentou ...201424214943
melioidosis presenting as lymphadenitis: a case report.melioidosis is an infection caused by the facultative intracellular gram-negative bacterium; burkholderia pseudomallei. it gives rise to protean clinical manifestations and has a varied prognosis. although it was rare in sri lanka increasing numbers of cases are being reported with high morbidity and mortality. here we report a case of melioidosis presenting with lymphadenitis which was diagnosed early and treated promptly with a good outcome.201424927768
melioidosis: molecular aspects of pathogenesis.burkholderia pseudomallei is a gram-negative bacterium that causes melioidosis, a multifaceted disease that is highly endemic in southeast asia and northern australia. this facultative intracellular pathogen possesses a large genome that encodes a wide array of virulence factors that promote survival in vivo by manipulating host cell processes and disarming elements of the host immune system. antigens and systems that play key roles in b. pseudomallei virulence include capsular polysaccharide, l ...201425312349
global analysis of the burkholderia thailandensis quorum sensing-controlled regulon.burkholderia thailandensis contains three acyl-homoserine lactone quorum sensing circuits and has two additional luxr homologs. to identify b. thailandensis quorum sensing-controlled genes, we carried out transcriptome sequencing (rna-seq) analyses of quorum sensing mutants and their parent. the analyses were grounded in the fact that we identified genes coding for factors shown previously to be regulated by quorum sensing among a larger set of quorum-controlled genes. we also found that genes c ...201424464461
nlrc4 and tlr5 each contribute to host defense in respiratory melioidosis.burkholderia pseudomallei causes the tropical infection melioidosis. pneumonia is a common manifestation of melioidosis and is associated with high mortality. understanding the key elements of host defense is essential to developing new therapeutics for melioidosis. as a flagellated bacterium encoding type iii secretion systems, b. pseudomallei may trigger numerous host pathogen recognition receptors. tlr5 is a flagellin sensor located on the plasma membrane. nlrc4, along with naip proteins, ass ...201425232720
neutrophil elastase causes tissue damage that decreases host tolerance to lung infection with burkholderia species.two distinct defense strategies can protect the host from infection: resistance is the ability to destroy the infectious agent, and tolerance is the ability to withstand infection by minimizing the negative impact it has on the host's health without directly affecting pathogen burden. burkholderia pseudomallei is a gram-negative bacterium that infects macrophages and causes melioidosis. we have recently shown that inflammasome-triggered pyroptosis and il-18 are equally important for resistance t ...201425166912
type three secretion system-mediated escape of burkholderia pseudomallei into the host cytosol is critical for the activation of nfκb.burkholderia pseudomallei is the causative agent of melioidosis, a potentially fatal disease endemic in southeast asia and northern australia. this gram-negative pathogen possesses numerous virulence factors including three "injection type" type three secretion systems (t3sss). b. pseudomallei has been shown to activate nfκb in hek293t cells in a toll-like receptor and myd88 independent manner that requires t3ss gene cluster 3 (t3ss3 or t3ssbsa). however, the mechanism of how t3ss3 contributes t ...201424884837
the bacterial aetiology of adult community-acquired pneumonia in asia: a systematic review.community-acquired pneumonia (cap) is a major cause of adult mortality in asia. appropriate empirical treatment depends on knowledge of the pathogens commonly responsible. however, assessing the aetiological significance of identified organisms is often difficult, particularly with sputum isolates that might represent contamination with oropharyngeal flora.201424781376
development of a prototype lateral flow immunoassay (lfi) for the rapid diagnosis of melioidosis.burkholderia pseudomallei is a soil-dwelling bacterium and the causative agent of melioidosis. isolation of b. pseudomallei from clinical samples is the "gold standard" for the diagnosis of melioidosis; results can take 3-7 days to produce. alternatively, antibody-based tests have low specificity due to a high percentage of seropositive individuals in endemic areas. there is a clear need to develop a rapid point-of-care antigen detection assay for the diagnosis of melioidosis. previously, we emp ...201424651568
etiologies and resistance profiles of bacterial community-acquired pneumonia in cambodian and neighboring countries' health care settings: a systematic review (1995 to 2012).community-acquired pneumonia (cap) is one of the most important causes of morbidity and mortality worldwide. etiological data for cambodia is scarce. we aimed to describe the main etiological agents causing cap, and their resistance patterns in cambodia and the greater mekong region.201424626053
characterization of an autotransporter adhesin protein shared by burkholderia mallei and burkholderia pseudomallei.autotransporters form a large family of outer membrane proteins specifying diverse biological traits of gram-negative bacteria. in this study, we report the identification and characterization of a novel autotransporter gene product of burkholderia mallei (locus tag bma1027 in strain atcc 23344).201424731253
pathogens penetrating the central nervous system: infection pathways and the cellular and molecular mechanisms of invasion.the brain is well protected against microbial invasion by cellular barriers, such as the blood-brain barrier (bbb) and the blood-cerebrospinal fluid barrier (bcsfb). in addition, cells within the central nervous system (cns) are capable of producing an immune response against invading pathogens. nonetheless, a range of pathogenic microbes make their way to the cns, and the resulting infections can cause significant morbidity and mortality. bacteria, amoebae, fungi, and viruses are capable of cns ...201425278572
burkholderia pseudomallei capsular polysaccharide conjugates provide protection against acute melioidosis.burkholderia pseudomallei, the etiologic agent of melioidosis, is a cdc tier 1 select agent that causes severe disease in both humans and animals. diagnosis and treatment of melioidosis can be challenging, and in the absence of optimal chemotherapeutic intervention, acute disease is frequently fatal. melioidosis is an emerging infectious disease for which there are currently no licensed vaccines. due to the potential malicious use of b. pseudomallei as well as its impact on public health in regi ...201424866807
protection against experimental melioidosis following immunisation with a lipopolysaccharide-protein conjugate.melioidosis is a severe infectious disease caused by burkholderia pseudomallei. it is refractory to antibiotic treatment and there is currently no licensed vaccine. in this report we detail the construction and protective efficacy of a polysaccharide-protein conjugate composed of b. pseudomallei lipopolysaccharide and the hc fragment of tetanus toxin. immunisation of mice with the lipopolysaccharide-conjugate led to significantly reduced bacterial burdens in the spleen 48 hours after challenge a ...201424892035
a burkholderia pseudomallei outer membrane vesicle vaccine provides protection against lethal sepsis.the environmental gram-negative encapsulated bacillus burkholderia pseudomallei is the causative agent of melioidosis, a disease associated with high morbidity and mortality rates in areas of southeast asia and northern australia in which the disease is endemic. b. pseudomallei is also classified as a tier i select agent due to the high level of lethality of the bacterium and its innate resistance to antibiotics, as well as the lack of an effective vaccine. gram-negative bacteria, including b. p ...201424671550
burkholderia pseudomallei penetrates the brain via destruction of the olfactory and trigeminal nerves: implications for the pathogenesis of neurological melioidosis.abstract melioidosis is a potentially fatal disease that is endemic to tropical northern australia and southeast asia, with a mortality rate of 14 to 50%. the bacterium burkholderia pseudomallei is the causative agent which infects numerous parts of the human body, including the brain, which results in the neurological manifestation of melioidosis. the olfactory nerve constitutes a direct conduit from the nasal cavity into the brain, and we have previously reported that b. pseudomallei can colon ...201424736221
variable virulence factors in burkholderia pseudomallei (melioidosis) associated with human disease.burkholderia pseudomallei is a gram-negative environmental bacterium that causes melioidosis, a potentially life-threatening infectious disease affecting mammals, including humans. melioidosis symptoms are both protean and diverse, ranging from mild, localized skin infections to more severe and often fatal presentations including pneumonia, septic shock with multiple internal abscesses and occasionally neurological involvement. several ubiquitous virulence determinants in b. pseudomallei have al ...201424618705
redefining the pf06864 pfam family based on burkholderia pseudomallei pilo2(bp) s-sad crystal structure.type iv pili are surface-exposed filaments and bacterial virulence factors, represented by the tfpa and tfpb types, which assemble via specific machineries. the tfpb group is further divided into seven variants, linked to heterogeneity in the assembly machineries. here we focus on pilo2(bp), a protein component of the tfpb r64 thin pilus variant assembly machinery from the pathogen burkholderia pseudomallei. pilo2(bp) belongs to the pf06864 pfam family, for which an improved definition is presen ...201424728008
culturable bacterial microbiota of the stomach of helicobacter pylori positive and negative gastric disease patients.human stomach is the only known natural habitat of helicobacter pylori (hp), a major bacterial pathogen that causes different gastroduodenal diseases. despite this, the impact of hp on the diversity and the composition of the gastric microbiota has been poorly studied. in this study, we have analyzed the culturable gastric microbiota of 215 malaysian patients, including 131 hp positive and 84 hp negative individuals that were affected by different gastric diseases. non-hp bacteria isolated from ...201425105162
inactivation of bacterial and viral biothreat agents on metallic copper surfaces.in recent years several studies in laboratory settings and in hospital environments have demonstrated that surfaces of massive metallic copper have intrinsic antibacterial and antiviral properties. microbes are rapidly inactivated by a quick, sharp shock known as contact killing. the underlying mechanism is not yet fully understood; however, in this process the cytoplasmic membrane is severely damaged. pathogenic bacterial and viral high-consequence species able to evade the host immune system a ...201425100640
construction and characterization of stable, constitutively expressed, chromosomal green and red fluorescent transcriptional fusions in the select agents, bacillus anthracis, yersinia pestis, burkholderia mallei, and burkholderia pseudomallei.here, we constructed stable, chromosomal, constitutively expressed, green and red fluorescent protein (gfp and rfp) as reporters in the select agents, bacillus anthracis, yersinia pestis, burkholderia mallei, and burkholderia pseudomallei. using bioinformatic approaches and other experimental analyses, we identified p0253 and p1 as potent promoters that drive the optimal expression of fluorescent reporters in single copy in b. anthracis and burkholderia spp. as well as their surrogate strains, r ...201425044501
cd4+ t cell epitopes of flic conserved between strains of burkholderia: implications for vaccines against melioidosis and cepacia complex in cystic fibrosis.burkholderia pseudomallei is the causative agent of melioidosis characterized by pneumonia and fatal septicemia and prevalent in southeast asia. related burkholderia species are strong risk factors of mortality in cystic fibrosis (cf). the b. pseudomallei flagellar protein flic is strongly seroreactive and vaccination protects challenged mice. we assessed b. pseudomallei flic peptide binding affinity to multiple hla class ii alleles and then assessed cd4 t cell immunity in hla class ii transgeni ...201425392525
the role of short-chain dehydrogenase/oxidoreductase, induced by salt stress, on host interaction of b. pseudomallei.burkholderia pseudomallei is the causative agent of melioidosis, a frequently occurring disease in northeastern thailand, where soil and water high in salt content are common. using microarray analysis, we previously showed that b. pseudomallei up-regulated a short-chain dehydrogenase/oxidoreductase (sdo) under salt stress. however, the importance of sdo in b. pseudomallei infection is unknown. this study aimed to explore the function of b. pseudomallei sdo, and to investigate its role in intera ...201424382268
galleria mellonella as an infection model for select agents.the use of animal models is a key step to better understand bacterial virulence factors and their roles in host/pathogen interactions. to avoid the ethical and cost problems of mammalian models in bacterial virulence research, several insect models have been developed. one of these models, the larvae of the greater wax moth galleria mellonella, has been shown to be relevant for several fungal and bacterial mammalian pathogens. here, we describe the use g. mellonella to study virulence of the hig ...201425172272
oropharyngeal aspiration of burkholderia mallei and burkholderia pseudomallei in balb/c mice.burkholderia mallei and burkholderia pseudomallei are potentially lethal pathogens categorized as biothreat agents due, in part, to their ability to be disseminated via aerosol. there are no protective vaccines against these pathogens and treatment options are limited and cumbersome. since disease severity is greatest when these agents are inhaled, efforts to develop pre- or post-exposure prophylaxis focus largely on inhalation models of infection. here, we demonstrate a non-invasive and technic ...201425503969
cross-species comparison of the burkholderia pseudomallei, burkholderia thailandensis, and burkholderia mallei quorum-sensing regulons.burkholderia pseudomallei, burkholderia thailandensis, and burkholderia mallei (the bptm group) are close relatives with very different lifestyles: b. pseudomallei is an opportunistic pathogen, b. thailandensis is a nonpathogenic saprophyte, and b. mallei is a host-restricted pathogen. the acyl-homoserine lactone quorum-sensing (qs) systems of these three species show a high level of conservation. we used transcriptome sequencing (rna-seq) to define the quorum-sensing regulon in each species, an ...201425182491
intramolecular aglycon delivery enables the synthesis of 6-deoxy-β-d-manno-heptosides as fragments of burkholderia pseudomallei and burkholderia mallei capsular polysaccharide.burkholderia pseudomallei and burkholderia mallei are potential bioterrorism agents. they express the same capsular polysaccharide (cps), a homopolymer featuring an unusual [→3)-2-o-acetyl-6-deoxy-β-d-manno-heptopyranosyl-(1→] as the repeating unit. this cps is known to be one of the main targets of the adaptive immune response in humans and therefore represents a crucial subunit candidate for vaccine development. herein, the stereoselective synthesis of mono- and disaccharidic fragments of the ...201424786555
evaluation of a latex agglutination assay for the identification of burkholderia pseudomallei and burkholderia mallei.cases of melioidosis and glanders are rare in the united states, but the etiologic agents of each disease (burkholderia pseudomallei and burkholderia mallei, respectively) are classified as tier 1 select agents because of concerns about their potential use as bioterrorism agents. a rapid, highly sensitive, and portable assay for clinical laboratories and field use is required. our laboratory has further evaluated a latex agglutination assay for its ability to identify b. pseudomallei and b. mall ...201424710616
the multiple roles of hypothetical gene bpss1356 in burkholderia pseudomallei.burkholderia pseudomallei is an opportunistic pathogen and the causative agent of melioidosis. it is able to adapt to harsh environments and can live intracellularly in its infected hosts. in this study, identification of transcriptional factors that associate with the β' subunit (rpoc) of rna polymerase was performed. the n-terminal region of this subunit is known to trigger promoter melting when associated with a sigma factor. a pull-down assay using histidine-tagged b. pseudomallei rpoc n-ter ...201424927285
production of a recombinant vaccine candidate against burkholderia pseudomallei exploiting the bacterial n-glycosylation machinery.vaccines developing immune responses toward surface carbohydrates conjugated to proteins are effective in preventing infection and death by bacterial pathogens. traditional production of these vaccines utilizes complex synthetic chemistry to acquire and conjugate the glycan to a protein. however, glycoproteins produced by bacterial protein glycosylation systems are significantly easier to produce, and could possible be used as vaccine candidates. in this work, we functionally expressed the burkh ...201425120536
mining locus tags in pubmed central to improve microbial gene annotation.the scientific literature contains millions of microbial gene identifiers within the full text and tables, but these annotations rarely get incorporated into public sequence databases. we propose to utilize the open access (oa) subset of pubmed central (pmc) as a gene annotation database and have developed an r package called pmcxml to automatically mine and extract locus tags from full text, tables and supplements.201424499370
pcr-based methodologies used to detect and differentiate the burkholderia pseudomallei complex: b. pseudomallei, b. mallei, and b. thailandensis.methods for the rapid detection and differentiation of the burkholderia pseudomallei complex comprising b. pseudomallei, b. mallei, and b. thailandensis, have been the topic of recent research due to the high degree of phenotypic and genotypic similarities of these species. b. pseudomallei and b. mallei are recognized by the cdc as tier 1 select agents. the high mortality rates of glanders and melioidosis, their potential use as bioweapons, and their low infectious dose, necessitate the need for ...201423969318
in situ hybridization to detect and identify burkholderia pseudomallei in human melioidosis.burkholderia pseudomallei causes a potentially fatal infection called melioidosis. we have developed a nonfluorescent, colorimetric in situ hybridization assay using a specific probe to target 16s rrna of b. pseudomallei in formalin-fixed, paraffin-embedded infected tissues for diagnostic purposes and to study infectious disease pathology. a 63-base pair dna probe was synthesized and labeled with digoxigenin by pcr. probe specificity was confirmed by blast analysis and by testing on appropriate ...201424186135
screen of whole blood responses to flagellin identifies tlr5 variation associated with outcome in melioidosis.melioidosis is a severe infection caused by the flagellated bacterium burkholderia pseudomallei. the nonsense polymorphism tlr51174c>t is associated with improved outcome in thais with melioidosis. we hypothesized that other tlr5 variants may modulate the host response and determine outcome in melioidosis. we genotyped 12 tlr5 variants selected de novo from the hapmap database and examined the association of each with cytokines induced by flagellin stimulation of whole blood from healthy thai su ...201424285178
trimethoprim-sulfamethoxazole versus trimethoprim-sulfamethoxazole plus doxycycline as oral eradicative treatment for melioidosis (merth): a multicentre, double-blind, non-inferiority, randomised controlled trial.melioidosis, an infectious disease caused by the gram-negative bacillus burkholderia pseudomallei, is difficult to cure. antimicrobial treatment comprises intravenous drugs for at least 10 days, followed by oral drugs for at least 12 weeks. the standard oral regimen based on trial evidence is trimethoprim-sulfamethoxaxole (tmp-smx) plus doxycycline. this regimen is used in thailand but is associated with side-effects and poor adherence by patients, and tmp-smx alone is recommended in australia. ...201424284287
influence of the molybdenum cofactor biosynthesis on anaerobic respiration, biofilm formation and motility in burkholderia thailandensis.burkholderia thailandensis is closely related to burkholderia pseudomallei, a bacterial pathogen and the causative agent of melioidosis. b. pseudomallei can survive and persist within a hypoxic environment for up to one year and has been shown to grow anaerobically in the presence of nitrate. currently, little is known about the role of anaerobic respiration in pathogenesis of melioidosis. using b. thailandensis as a model, a library of 1344 transposon mutants was created to identify genes requi ...201424239959
the role of nod2 in murine and human melioidosis.nucleotide-binding oligomerization domain 2 (nod2) is a cytosolic pathogen recognition receptor that regulates susceptibility to a variety of infections and chronic diseases. burkholderia pseudomallei, a facultative intracellular bacterium, causes the tropical infection melioidosis. we hypothesized that nod2 may participate in host defense in melioidosis. we performed a series of in vitro assays and in vivo experiments and analyzed the association of human genetic variation with infection to del ...201424298015
activation of nadph oxidase is essential, but not sufficient, in controlling intracellular multiplication of burkholderia pseudomallei in primary human monocytes.burkholderia pseudomallei is a gram-negative intracellular bacterium and the causative agent of melioidosis. innate immune mechanisms against this pathogen, which might contribute to outcomes of melioidosis, are little known. we demonstrated here that b. pseudomallei could activate nadph oxidase in primary human monocytes as judged by production of reactive oxygen species (ros) and p40(phox) phosphorylation after infection. however, as similar to other intracellular bacteria, this bacterium was ...201424376210
osteomyelitis caused by burkholderia pseudomallei: relapse six years after pulmonary infection.burkholderia pseudomallei is highly endemic in southeast asia, whereas in europe usually only few imported cases of melioidosis occur.201425291954
autochthonous melioidosis in humans, madagascar, 2012 and 2013.melioidosis is an often fatal infectious disease affecting humans and animals in the tropics. only sporadic cases have been reported from africa and the indian ocean region. we describe 2 confirmed autochthonous cases of human melioidosis in madagascar, both from novel genotypes of burkholderia pseudomallei.201425272365
mice lacking the lectin-like domain of thrombomodulin are protected against melioidosis.thrombomodulin is a multidomain receptor primarily expressed by vascular endothelium. the lectin-like domain of thrombomodulin has anti-inflammatory properties. in this study, we investigated the role of the thrombomodulin lectin-like domain in the host response to gram-negative sepsis caused by burkholderia pseudomallei, a "tier 1" biothreat agent and the causative agent of melioidosis, a common form of community-acquired sepsis in southeast asia.201424399241
common tlr1 genetic variation is not associated with death from melioidosis, a common cause of sepsis in rural thailand.melioidosis, infection caused by the gram-negative bacterium burkholderia pseudomallei, is a common cause of sepsis in northeast thailand. in white north americans, common functional genetic variation in tlr1 is associated with organ failure and death from sepsis. we hypothesized that tlr1 variants would be associated with outcomes in thais with melioidosis. we collated the global frequencies of three tlr1 variants that are common in white north american populations: rs5743551 (-7202a/g), rs4833 ...201424392083
a multiplex nested pcr for the simultaneous detection of salmonella typhi, mycobacterium tuberculosis, and burkholderia pseudomallei in patients with pyrexia of unknown origin (puo) in vellore, south india.salmonella typhi, mycobacterium tuberculosis, and burkholderia pseudomallei are among the most important monocyte-tropic bacterial agents causing pyrexia of unknown origin (puo), with a significant number of endemic infections in both south and southeast asian regions. these infections pose a major risk to travelers to these regions as well.201424385404
pathogenesis of percutaneous infection of goats with burkholderia pseudomallei: clinical, pathologic, and immunological responses in chronic melioidosis.melioidosis is a severe suppurative to granulomatous infection caused by burkholderia pseudomallei. the disease is endemic to south-east asia and northern australasia and is also of interest as a potential biological weapon. natural infection can occur by percutaneous inoculation, inhalation or ingestion, but the relative importance of each route is unknown. experimental infection models using mice have shown inhalation to be the most lethal route of exposure, but few studies have examined the p ...201424571408
wound healing activity and mechanisms of action of an antibacterial protein from the venom of the eastern diamondback rattlesnake (crotalus adamanteus).basic phospholipase a2 was identified from the venom of the eastern diamondback rattlesnake. the crotalus adamanteus toxin-ii (catx-ii) induced bactericidal effects (7.8 µg/ml) on staphylococcus aureus, while on burkholderia pseudomallei (khw), and enterobacter aerogenes were killed at 15.6 µg/ml. catx-ii caused pore formation and membrane damaging effects on the bacterial cell wall. catx-ii was not cytotoxic on lung (mrc-5), skin fibroblast (hepk) cells and in mice. catx-ii-treated mice showed ...201424551028
whitmore's disease: an uncommon urological presentation.the incidence of prostatic abscesses has much decreased in the antibiotic era. we present an uncommon cause of prostatic abscess secondary to melioidosis, also known as whitmore's disease or pseudoglanders. the disease is endemic in south east asia and australia. although india is considered endemic for burkholderia pseudomallei, the causative organism of melioidosis, not many cases have been reported. most of the reported cases from india are from the south-west coastal regions of kerala and ka ...201424518392
colonization or spontaneous resolution: expanding the role for burkholderia pseudomallei.a 19-year-old asian indian female presented with productive cough since the past one month and low grade fever since the past two weeks. she was diagnosed with pulmonary tuberculosis and treated with antitubercular drugs. subsequently, delayed cultures of bronchoalveolar lavage fluid grew burkholderia pseudomallei (b. pseudomallei). on follow up the patient reported significant subjective improvement and esr progressively returned to normal. in summary, this case report raises two distinct and e ...201424507650
in vitro activity of ceftaroline against burkholderia pseudomallei. 201424505090
structural characterization of polysaccharides expressed by burkholderia oklahomensis e0147.burkholderia oklahomensis e0147 is a us isolated bacterium believed to express a similar o-antigen to type a structure of the highly pathogenic species, burkholderia pseudomallei. both species are genetically closely related. lipopolysaccharide was collected from e0147 and structurally characterized to test this hypothesis. glycosyl composition and linkage analyses in conjunction with 1d and 2d (1)h and (13)c nmr spectroscopy showed that the o-antigen was a repeating disaccharide with the follow ...201424491843
recurrent melioidosis in the darwin prospective melioidosis study: improving therapies mean that relapse cases are now rare.the darwin prospective melioidosis study has documented 785 melioidosis cases over 23 years. recurrent melioidosis occurred in 39/679 (5.7%) patients surviving initial infection; 29 patients suffered relapse of the original infection, and 10 presented with a new burkholderia pseudomallei infection. with improved therapy, relapse has become rare in recent years.201424478504
the serine protease inhibitor ecotin is required for full virulence of burkholderia pseudomallei.burkholderia pseudomallei is a gram negative soil saprophyte that causes the disease melioidosis where clinical symptoms can vary from localised infection to pneumonia and septic shock. ecotin is a potent periplasmic serine protease inhibitor first identified in escherichia coli. ecotin, although present in only a small subset of genera, can inhibit a broad range of serine proteases including those typically associated with the innate immune system such as neutrophil elastase and cathepsin g. an ...201424462575
melioidosis of salivary glands with coexisting diabetes: management of a difficult case.melioidosis is an infectious disease caused by the gram-negative bacillus burkholderia pseudomallei. melioidosis is endemic in southeast asia and northern australia. an important risk factor for the development of melioidosis is the presence of diabetes mellitus, which may increase the relative risk of infection by as much as 100-fold. we report a rare case of melioidosis of the parotid and submandibular gland with coexisting diabetes. this was successfully managed conservatively with intravenou ...201424452899
vgrg-5 is a burkholderia type vi secretion system-exported protein required for multinucleated giant cell formation and virulence.the type vi secretion system (t6ss) has emerged as a critical virulence factor for the group of closely related burkholderia spp. that includes burkholderia pseudomallei, b. mallei, and b. thailandensis. while the genomes of these bacteria, referred to as the bptm group, appear to encode several t6sss, we and others have shown that one of these, type vi secretion system 5 (t6ss-5), is required for virulence in mammalian infection models. despite its pivotal role in the pathogenesis of the bptm g ...201424452686
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