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In silico Annotation of the Genes Involved in Biosynthesis of Lipopolysaccharide for Burkholderia pseudomallei
Lai L. Suang,Zamberi Sekawi,Nagi A. Al-Haj,Mariana N. Shamsudin,Rasedee Abdullah,Rahmah Mohamed
Research Journal of Applied Sciences , 2012,
Abstract: Burkholderia pseudomallei is the causative agent of melioidosis, a serious disease of man and animals. The high mortality of B. pseudomallei infections may cause by lipopolysaccharides, an endotoxin. The biosynthesis of LPS is complex comprising three components, lipid A, core oligosaccharide and O-specific antigen. In the current study, by using the available B. pseudomallei genome database provided by Wellcome. The study demonstrated that the bioinformatics comparative technique was able to annotate LPS genes in Burkholderia pseudomallei. By developing a simple and easy flow chart including the using of Artemis software, total of 44 putative ORFs involved in biosynthesis of lipopolysaccharide for B. pseudomallei and the genetic mapping for the ORFs have been successfully determined using bioinformatics and laboratory approach. It is about 95.7% of success for annotation based on the 46 genes that act as references. In near future, a suitable vaccine or antimicrobial may be developed by targeting the genes encoding the various components essential in LPS biosynthesis and survival of the pathogen.
Innate Immune Responses of Pulmonary Epithelial Cells to Burkholderia pseudomallei Infection  [PDF]
Siew Hoon Sim, Yichun Liu, Dongling Wang, Vidhya Novem, Suppiah Paramalingam Sivalingam, Tuck Weng Thong, Eng Eong Ooi, Gladys Tan
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0007308
Abstract: Background Burkholderia pseudomallei, a facultative intracellular pathogen, causes systemic infection in humans with high mortality especially when infection occurs through an infectious aerosol. Previous studies indicated that the epithelial cells in the lung are an active participant in host immunity. In this study, we aimed to investigate the innate immune responses of lung epithelial cells against B. pseudomallei. Methodology and Principal Findings Using a murine lung epithelial cell line, primary lung epithelial cells and an inhalational murine infection model, we characterized the types of innate immunity proteins and peptides produced upon B. pseudomallei infection. Among a wide panel of immune components studied, increased levels of major pro-inflammatory cytokines IL-6 and TNFα, chemokine MCP-1, and up-regulation of secretory leukocyte protease inhibitor (SLPI) and chemokine (C-C motif) ligand 20 (CCL20) were observed. Inhibition assays using specific inhibitors suggested that NF-κB and p38 MAPK pathways were responsible for these B. pseudomallei-induced antimicrobial peptides. Conclusions Our findings indicate that the respiratory epithelial cells, which form the majority of the cells lining the epithelial tract and the lung, have important roles in the innate immune response against B. pseudomallei infection.
The Genetic and Molecular Basis of O-Antigenic Diversity in Burkholderia pseudomallei Lipopolysaccharide  [PDF]
Apichai Tuanyok ,Joshua K. Stone,Mark Mayo,Mirjam Kaestli,Jeffrey Gruendike,Shalamar Georgia,Stephanie Warrington,Travis Mullins,Christopher J. Allender,David M. Wagner,Narisara Chantratita,Sharon J. Peacock,Bart J. Currie,Paul Keim
PLOS Neglected Tropical Diseases , 2012, DOI: 10.1371/journal.pntd.0001453
Abstract: Lipopolysaccharide (LPS) is one of the most important virulence and antigenic components of Burkholderia pseudomallei, the causative agent of melioidosis. LPS diversity in B. pseudomallei has been described as typical, atypical or rough, based upon banding patterns on SDS-PAGE. Here, we studied the genetic and molecular basis of these phenotypic differences. Bioinformatics was used to determine the diversity of genes known or predicted to be involved in biosynthesis of the O-antigenic moiety of LPS in B. pseudomallei and its near-relative species. Multiplex-PCR assays were developed to target diversity of the O-antigen biosynthesis gene patterns or LPS genotypes in B. pseudomallei populations. We found that the typical LPS genotype (LPS genotype A) was highly prevalent in strains from Thailand and other countries in Southeast Asia, whereas the atypical LPS genotype (LPS genotype B) was most often detected in Australian strains (~13.8%). In addition, we report a novel LPS ladder pattern, a derivative of the atypical LPS phenotype, associated with an uncommon O-antigen biosynthesis gene cluster that is found in only a small B. pseudomallei sub-population. This new LPS group was designated as genotype B2. We also report natural mutations in the O-antigen biosynthesis genes that potentially cause the rough LPS phenotype. We postulate that the diversity of LPS may correlate with differential immunopathogenicity and virulence among B. pseudomallei strains.
Genes Expression in Biosynthesis Lipopolysaccharide of Burkholderia pseudomallei the Causative Agent of Melioidosis
Nagi A. Al-Haj,Lai L. Suang,Mariana N. Shamsudin,Rasedee Abdullah,Rahmah Mohamed,Zamberi Sekawi
Research Journal of Biological Sciences , 2012,
Abstract: Burkholderia pseudomallei is the causative agent of melioidosis, a serious disease of man and animals. The high mortality of B. pseudomallei infections may cause by Lipopolysaccharides (LPS), an endotoxin. The biosynthesis of LPS is complex comprising three components, lipid A, core oligosaccharide and O-specific antigen. In the current study was designed to further elucidate genes involved in the biosynthesis pathway of LPS in melioidosis agent followed with selected gene product expression with essential function for survival and virulence melioidosis agent. Expression of Bplps0013/lpxA and Bplps0007/rfaF successful expressed the entire proteins in 2 h with sizes of approximately 29 kDa and 43.7 kDa, respectively. The baseline information provided through the present research can be a preliminary approach towards the development of effective therapeutics against melioidosis.
Nasal Acai Polysaccharides Potentiate Innate Immunity to Protect against Pulmonary Francisella tularensis and Burkholderia pseudomallei Infections  [PDF]
Jerod A. Skyberg ,MaryClare F. Rollins,Jeff S. Holderness,Nicole L. Marlenee,Igor A. Schepetkin,Andrew Goodyear,Steven W. Dow,Mark A. Jutila,David W. Pascual
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002587
Abstract: Pulmonary Francisella tularensis and Burkholderia pseudomallei infections are highly lethal in untreated patients, and current antibiotic regimens are not always effective. Activating the innate immune system provides an alternative means of treating infection and can also complement antibiotic therapies. Several natural agonists were screened for their ability to enhance host resistance to infection, and polysaccharides derived from the Acai berry (Acai PS) were found to have potent abilities as an immunotherapeutic to treat F. tularensis and B. pseudomallei infections. In vitro, Acai PS impaired replication of Francisella in primary human macrophages co-cultured with autologous NK cells via augmentation of NK cell IFN-γ. Furthermore, Acai PS administered nasally before or after infection protected mice against type A F. tularensis aerosol challenge with survival rates up to 80%, and protection was still observed, albeit reduced, when mice were treated two days post-infection. Nasal Acai PS administration augmented intracellular expression of IFN-γ by NK cells in the lungs of F. tularensis-infected mice, and neutralization of IFN-γ ablated the protective effect of Acai PS. Likewise, nasal Acai PS treatment conferred protection against pulmonary infection with B. pseudomallei strain 1026b. Acai PS dramatically reduced the replication of B. pseudomallei in the lung and blocked bacterial dissemination to the spleen and liver. Nasal administration of Acai PS enhanced IFN-γ responses by NK and γδ T cells in the lungs, while neutralization of IFN-γ totally abrogated the protective effect of Acai PS against pulmonary B. pseudomallei infection. Collectively, these results demonstrate Acai PS is a potent innate immune agonist that can resolve F. tularensis and B. pseudomallei infections, suggesting this innate immune agonist has broad-spectrum activity against virulent intracellular pathogens.
Genome wide transcriptome profiling of a murine acute melioidosis model reveals new insights into how Burkholderia pseudomallei overcomes host innate immunity
Chui-Yoke Chin, Denise M Monack, Sheila Nathan
BMC Genomics , 2010, DOI: 10.1186/1471-2164-11-672
Abstract: Viable B. pseudomallei cells were consistently detected in the blood, liver and spleen during the 42 hr course of infection. Microarray analysis of the liver and spleen over this time course demonstrated that genes involved in immune response, stress response, cell cycle regulation, proteasomal degradation, cellular metabolism and signal transduction pathways were differentially regulated. Up regulation of toll-like receptor 2 (TLR2) gene expression suggested that a TLR2-mediated signalling pathway is responsible for recognition and initiation of an inflammatory response to the acute B. pseudomallei infection. Most of the highly elevated inflammatory genes are a cohort of "core host immune response" genes commonly seen in general inflammation infections. Concomitant to this initial inflammatory response, we observed an increase in transcripts associated with cell-death, caspase activation and peptidoglysis that ultimately promote tissue injury in the host. The complement system responsible for restoring host cellular homeostasis and eliminating intracellular bacteria was activated only after 24 hr post-infection. However, at this time point, diverse host nutrient metabolic and cellular pathways including glycolysis, fatty acid metabolism and tricarboxylic acid (TCA) cycle were repressed.This detailed picture of the host transcriptional response during acute melioidosis highlights a broad range of innate immune mechanisms that are activated in the host within 24 hrs, including the core immune response commonly seen in general inflammatory infections. Nevertheless, this activation is suppressed at 42 hr post-infection and in addition, suboptimal activation and function of the downstream complement system promotes uncontrolled spread of the bacteria.How organisms respond appropriately to B. pseudomallei, the causative agent of melioidosis, remains a central question within the Burkholderia community. Over the past decade, knowledge on the pathogenesis of B. pseudomalle
The innate interferon gamma response of BALB/c and C57BL/6 mice to in vitro Burkholderia pseudomallei infection
Ghee Koo, Yunn-Hwen Gan
BMC Immunology , 2006, DOI: 10.1186/1471-2172-7-19
Abstract: Na?ve BALB/c splenocytes were found to produce more IFN-γ in response to live bacterial infection compared to C57BL/6 splenocytes. Natural killer cells were found to be the major producers of IFN-γ, while T cells and Gr-1intermediate cells also contributed to the IFN-γ response. Although anti-Gr-1 depletion substantially reduced the IFN-γ response, this was not due to the contribution of Gr-1high, Ly-6G expressing neutrophils. We found no differences in the cell types making IFN-γ between BALB/c and C57BL/6 splenocytes. Although IL-12 is essential for the IFN-γ response, BALB/c and C57BL/6 splenocytes made similar amounts of IL-12 after infection. However, BALB/c splenocytes produced higher proinflammatory cytokines such as IL-1β, TNF-α, IL-6, IL-18 than C57BL/6 splenocytes after infection with B. pseudomallei.Higher percentages of Gr-1 expressing NK and T cells, poorer ability in controlling bacteria growth, and higher IL-18 could be the factors contributing to IFN-γ hyperproduction in BALB/c mice.Burkholderia pseudomallei is the causative agent for melioidosis, an infectious disease endemic in South-east Asia and northern Australia [1,2]. It has also been increasingly reported in other tropical and subtropical regions [3]. The bacillus is a facultative intracellular microbe and can invade and replicate in many different organs. Infection can result in a wide spectrum of clinical outcomes, ranging from an asymptomatic state, benign pulmonitis, acute or chronic pneumonia, and to fulminant septicemias [4]. Furthermore, even after the apparent resolution of acute symptoms, the infection can persist for decades as a chronic and latent condition where relapse is possible [5]. Despite appropriate antibiotic treatment, severe melioidosis with acute septicemia is associated with a high mortality rate [6].In severe melioidosis, patients exhibit elevated serum levels of proinflammatory cytokines such as TNF-α [7], IFN-γ [8] and IFN-γ induced chemokines IP-10 and MIG [9]. Mur
Development of Burkholderia mallei and pseudomallei vaccines  [PDF]
Ediane B. Silva,Steven W. Dow
Frontiers in Cellular and Infection Microbiology , 2013, DOI: 10.3389/fcimb.2013.00010
Abstract: 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-specific, making diagnosis difficult. B. pseudomallei can be located in the environment, but in the host, B. mallei and B. psedomallei are intracellular organisms, and infection results in similar immune responses to both agents. Effective early innate immune responses are critical to controlling the early phase of the infection. Innate immune signaling molecules such as TLR, NOD, MyD88, and pro-inflammatory cytokines such as IFN-γ and TNF-α play key roles in regulating control of infection. Neutrophils and monocytes are critical cells in the early infection for both microorganisms. Both monocytes and macrophages are necessary for limiting dissemination of B. pseudomallei. In contrast, the role of adaptive immune responses in controlling Burkholderia infection is less well understood. However, T cell responses are critical for vaccine protection from Burkholderia infection. At present, effective vaccines for prevention of glanders or meliodosis have not been developed, although recently development of Burkholderia vaccines has received renewed attention. This review will summarize current and past approaches to develop B. mallei and B. pseudomalllei vaccines, with emphasis on immune mechanisms of protection and the challenges facing the field. At present, immunization with live attenuated bacteria provides the most effective and durable immunity, and it is important therefore to understand the immune correlates of protection induced by live attenuated vaccines. Subunit vaccines have typically provided less robust immunity, but are safer to administer to a wider variety of people, including immune compromised individuals because they do not reactivate or cause disease. The challenges facing B. mallei and B. pseudomalllei vaccine development include identification of broadly protective antigens, design of efficient vaccine delivery and adjuvant systems, and a better understanding of the correlates of protection from both acute and chronic infection.
Survival of Burkholderia pseudomallei in Water
Richard A Moore, Apichai Tuanyok, Donald E Woods
BMC Research Notes , 2008, DOI: 10.1186/1756-0500-1-11
Abstract: Increased expression of a gene encoding for a putative membrane protein (BPSL0721) was confirmed using a lux-based transcriptional reporter system, and maximal expression was noted at approximately 6 hrs after shifting cells from LB to water. A BPSL0721 deficient mutant of B. pseudomallei was able to survive in water for at least 90 days indicating that although involved, BPSL0721 was not essential for survival. BPSL2961, a gene encoding a putative phosphatidylglycerol phosphatase (PGP), was also induced when cells were shifted to water. This gene is likely involved in cell membrane biosynthesis. We were unable to construct a PGP mutant suggesting that the gene is not only involved in survival in water but is essential for cell viability. We also examined mutants of polyhydroxybutyrate synthase (phbC), lipopolysaccharide (LPS) oligosaccharide and capsule synthesis, and these mutations did not affect survival in water. LPS mutants lacking outer core were found to lose viability in water by 200 days indicating that an intact LPS core provides an outer membrane architecture which allows prolonged survival in water.The results from these studies suggest that B. pseudomallei survival in water is a complex process that requires an LPS molecule which contains an intact core region.Burkholderia pseudomallei is the causative agent of melioidosis, a disease endemic to southeast Asia, northern Australia and temperate areas that lie near the equator[1]. The disease is classified by acute, subacute and chronic illnesses and often mistaken for malaria, plague, pneumonia and miliary tuberculosis [2]. The acute form of the disease is a septicemic illness and is often fatal despite antibiotic treatment. Subacute meliodosis often results in multi-organ involvement, systemic abscess formation and bacteremia [3]. Chronic meliodosis often is detected only after post mortem examination or by activation of other forms of the disease as a result of a traumatic event [4]. Infection most lik
Autotransporters and Their Role in the Virulence of Burkholderia pseudomallei and Burkholderia mallei  [PDF]
Joanne M. Stevens,Edouard E. Galyov
Frontiers in Microbiology , 2011, DOI: 10.3389/fmicb.2011.00151
Abstract: Burkholderia pseudomallei and Burkholderia mallei are closely related Gram-negative bacteria responsible for the infectious diseases melioidosis and glanders, respectively. Autotransporters (ATs) comprise a large and diverse family of secreted and outer membrane proteins that includes virulence-associated invasins, adhesins, proteases, and actin-nucleating factors. The B. pseudomallei K96243 genome contains 11 predicted ATs, eight of which share homologs in the B. mallei ATCC 23344 genome. This review distils key findings from in silico, in vitro, and in vivo studies on the ATs of B. pseudomallei and B. mallei. To date, the best characterized of the predicted ATs of B. pseudomallei and B. mallei is BimA, a predicted trimeric AT mediating actin-based motility which varies in sequence and mode of action between Burkholderia species. Of the remaining eight predicted B. pseudomallei trimeric autotransporters, five of which are also present in B. mallei, two (BoaA and BoaB), have been implicated in bacterial adhesion to epithelial cells. Several predicted Burkholderia ATs are recognized by human humoral and cell-mediated immunity, indicating that they are expressed during infection and may be useful for diagnosis and vaccine-mediated protection. Further studies on the mode of secretion and functions of Burkholderia ATs will facilitate the rational design of control strategies.
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