Pathogenesis of Burkholderia pseudomallei and Burkholderia mallei

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1 MILITARY MEDICINE, 174, 6:647, 2009 Pathogenesis of Burkholderia pseudomallei and Burkholderia mallei Joseph C. Larsen, PhD ; Lt Col Nathan H. Johnson, USAF BSC ABSTRACT Burkholderia pseudomallei and mallei are biological agents of military significance. There has been significant research in recent years to develop medical countermeasures for these organisms. This review summarizes work which details aspects of the pathogenesis of B. psuedomallei and mallei and discusses key scientific questions and directions for future research. INTRODUCTION Burkholderia pseudomallei is a gram negative, facultatively anaerobic, motile Bacillus that is the causative agent of melioidosis. The bacterium is a soil saprophyte, often present in wet soils and rice paddies in Southeast Asia. Melioidosis occurs after the organism contaminates superficial breaks in the skin or via inhalation. The clinical presentation of melioidosis ranges from an acute febrile illness to disseminated septicemia. 1 The septicemic form of infection is rapidly fatal, with a mortality rate of approximately 40%, and death occurrs hours following the onset of symptoms. 2 Abscess formation in the lungs, liver, spleen, and skeletal muscles are the hallmarks of infection. Subclinical infections may reactivate after numerous years of dormancy. Impairment of the immune system, diabetes, alcoholism, renal disease, malignancies, steroid therapy, and tuberculosis are all risk factors for melioidosis. 3 B. mallei is a gram negative, aerobic, nonmotile Bacillus that causes glanders. It is a host-adapted pathogen that is not capable of environmental persistence. Because of quarantine and other measures, glanders has been eradicated from most countries. Small pockets of zoonotic endemicity still exist in the Middle East, Asia, Africa, and South America. 6 Glanders is highly transmissible among solipeds ( horses, donkeys, and mules). In horses, acute glanders presents as fever accompanied by necrotic ulcers and nodules in the nasal passages. Lymph nodes of the neck and mediastinal regions are enlarged and pneumonia with dissemination to internal organs can occur. In humans, the disease can be acute or chronic. With respiratory exposure, acute febrile illness with ulcerative necrosis of the upper respiratory tract can occur. Patients present with mucopurulent discharge from the nose, Defense Threat Reduction Agency/Joint Science and Technology Office for Chemical and Biological Defense, 8725 John Kingman Road, Fort Belvoir, VA The opinions or assertions contained herein are the private views of the author and are not to be construed as reflecting the Defense Threat Reduction Agency or the Department of Defense. This manuscript was received for review in August The revised manuscript was accepted for publication in February lips, and eyes. Neck and mediastinal lymphadenopathy, pustular skin lesions, and septicemia can follow. 6 Both B. pseudomallei and mallei are classified as category B bioterrorism agents by the Centers for Disease Control and Prevention (CDC). Currently the Defense Threat Reduction Agency s (DTRA) Joint Science and Technology Office for Chemical and Biological Defense (JSTO-CBD) is supporting research to develop novel medical countermeasures for B. pseudomallei and mallei. Basic research to identify therapeutic targets as well as applied efforts to develop vaccines and antimicrobial therapies are ongoing research areas. Specifically, DTRA/JSTO is supporting the testing and evaluation of the Food and Drug Administration s (FDA) approved antibiotics, the development of nonhuman primate aerosol challenge models that mimic the pathology of Burkholderia infection, and the advancement of novel monoclonal antibody and vaccine platforms. Future research will determine the molecular mechanisms of Burkholderia persistence within the host. Candidate medical countermeasures have been developed that possess some efficacy against aerosol challenge in the mouse model. 4,5 However, sterilizing immunity has not been achieved with any of these candidates. Discovery of the molecular mechanisms of Burkholderia s persistence in the host and the induction of sterilizing immunity are important research goals for the program. B. mallei was introduced as a biological weapon early in the twentieth century. 6 During the First World War, German sympathizers in various countries infected equine destined for conflict areas with B. mallei. 7 9 Combat operations were affected by infection of humans and equines. 10 In 1925, the Geneva Protocol prohibited the use of bacteriological warfare. 9 The Soviet Union and Japan studied the use of B. mallei before the Second World War. 8,9 During the Second World War, the Japanese infected Chinese prisoners with B. mallei. 9 Several countries, including the United States and the Soviet Union, studied B. pseudomallei for potential offensive intent. 11,12 In 1972, the Convention on the Prohibition of the Development, Production, and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on Their Destruction, was introduced. 8 The Soviet Union was accused of using B. mallei in Afghanistan in the early 1980s. 9 There have been MILITARY MEDICINE, Vol. 174, June

2 no reports of the malicious use B. mallei or B. pseudomallei in recent years. At present, there are no FDA approved antimicrobials for postexposure prophylaxis or treatment for B. pseudomallei or mallei infection. All antibiotics used for treatment would be used off-label or would be granted emergency use authorization status by the FDA. Treatment of B. pseudomallei is difficult because of its natural resistance to a number of antibiotics. The presence of several multidrug efflux pumps implicated in resistance to aminoglycoside and macrolide antibiotics in B. pseudomallei have been reported. 13,14 Typically, B. pseudomallei are sensitive to trimethoprim-sulfamethoxazole, chloramphenicol, tetracyclines, third generation cephalosporins, car bapenems, and amoxicillin-clavulanate. 1 The antibiotic sensitivity profile of B. mallei is similar to B. pseduomaleii, except that B. mallei is sensitive to gentamicin and certain macrolides (clarithromycin, azithromycin) although B. pseudomallei is resistant. 6 GENOMICS The genomes of B. pseudomallei and mallei have been sequenced.15,16 The B. pseudomallei genome consists of two chromosomes of 4.07 and 3.17 Mb. There is evidence of significant horizontal gene transfer, indicated by the presence of 16 different genomic islands distributed across the genome. These regions possess homology to genes associated with mobile genetic elements, such as insertion sequences, plasmids, and bacteriophage. The B. pseduomallei genome contains multiple genes predicted to be involved in environmental survival and virulence. Drug resistance genes, including predicted drug efflux pumps, β -lactamases, and aminoglycoside acetyltransferases were identified, reflecting the intrinsic high levels of drug resistance exhibited by B. pseudomallei. Numerous protein secretion systems typically involved in pathogenesis of other bacterial agents were identified in the genome of B. pseudomallei. Several protein secretion systems (types I, II, and V) and three type III secretion systems (T3SS) are predicted in the genome. Genes predicted to encode cell surface adhesion proteins and fimbrae were also detected. 15 The B. mallei genome is significantly smaller than B. pseduomallei, consisting of 5.7 Mb distributed across two chromosomes (3.5 and 2.3 Mb). The genome harbors insertion elements that account for approximately 3.1% of the genome. These elements likely mediate the extensive genomewide insertion, deletion, and rearrangements that have resulted in the genome reduction relative to B. pseudomallei. Approximately 1,400 genes present in B. pseudomallei are either missing or are variant in B. mallei. Flagellar and chemotaxis genes, for example, have undergone frameshift or insertional mutation, resulting in defective proteins critical for function. This suggests that portions of the B. mallei genome are undergoing active genomic decay, possibly to further acclimate to a lifestyle within a mammalian host. 16 Comparative analysis of B. pseduomallei and B. mallei with other nonpathogenic Burkholderia species provides insight in the mechanism of divergence and evolution of these organisms. All isolates of the nonpathogenic B. thailandensis can utilize L-arabinose as a sole carbon source, although B. pseudomallei cannot. Analysis of the B. pseudomallei and B. mallei chromosome revealed the presence of a deletion of the arabinose operon in all strains examined. 17 The entire B. thailandensis arabinose operon was cloned into B. pseduomallei. The resulting strain had a decrease in virulence (25- to 50-fold) in the Syrian hamster model compared to the parent, wild-type strain. 17 Microarray analysis revealed that a number of genes in the type III secretion system (T3SS) were downregulated when cultured in the presence of arabinose. This suggests that the loss of the genes for the metabolism of arabinose was a pathoadaptive mutation that may provide B. pseudomallei with a selective advantage for survival in animal hosts. 17 Similar pathoadaptive mutations are present in a number of bacterial pathogens, suggesting that the loss of genes incompatible with a pathogenic lifestyle is a common mechanism of niche adaptation. 18 A number of studies have been conducted to determine genes required for virulence or host survival ( Table I ). Transposon mutagenesis was utilized to screen for mutants attenuated in their ability to invade cells in vitro and survive in vivo. 19,20 Mutant genes involved in amino acid biosynthesis, capsular polysaccharide synthesis, DNA replication and repair, a putative lipoprotein, ABC transporters, and a putative oxidoreductase were found to be significantly attenuated in vivo, suggesting that these pathways play a critical role in allowing for survival and replication within the mammalian host. TABLE I. Bacterial Factors Implicated in the Pathogenesis of Burkholderia pseduomallei and mallei Putative Virulence Factor Mutant Phenotype Mechanism Reference Capsule Attenuation in mouse and Syrian hamster models; Prevention of opsonization by complement 20, 21, 22 reduced ability to survive in serum Type III Secretion Systems Attenuation in mouse and Syrian hamster models; Few secretion substrates identified. BopE 24, 25, 27 reduced ability to invade nonphagocytic cells; reduced intracellular growth within macrophages; phagosomal escape induces cytoskeletal rearrangements BimA (Autotransporter) Inability to form membrane protrusions in vitro; no Stimulation of the Arp2/3 complex/actin 31, 34 attenuation in virulence in Syrian hamster model polymerization for intracellular motility Type VI Secretion Systems Attenuation in Syrian hamster model Unknown, Hcp1 identified as a secreted protein 34 Quorum Sensing (QS) Attenuation in mouse and Syrian hamster models; decreased organ colonization Identity of genes regulated by QS system remains unknown 37, MILITARY MEDICINE, Vol. 174, June 2009

3 Recently, a set of 650 putative B. psuedomallei and mallei virulence-related genes were compiled utilizing a computerbased analysis of the genomes of B. psuedomallei, mallei, and 5 nonpathogenic Burkholderia species. To rapidly evaluate these mutants in an animal model, a wax moth ( Galleria mellonella ) larvae system was developed. 21 Pathogenic strains of B. psuedomallei and mallei, but not nonpathogenic-related bacteria, were found to be highly pathogenic for this insect. Three new mutants in B. mallei were identified that were reduced in their lethality in the wax moth larval model. These genes encoded proteins with homology to a polyketide synthase, a putative exported protein in Bordetella bronchiseptica, and a protein involved in amino acid biosynthesis. 21 Expression analysis of B. psuedomallei in the Syrian hamster was conducted to determine the bacterial genes that are upor downregulated in the mammalian host. 22 Syrian hamsters were administered intraperitoneal or intranasal challenges of B. pseudomallei, liver, lungs, and spleens were collected, and expression analysis performed using whole genome microarray. Expression levels were compared to bacteria grown in culture broth. In concurrence with the aforementioned study, genes for specific energy production pathways and amino acid biosynthesis were upregulated. A phospholipase C, which is a virulence factor in several other bacterial species and a two-component regulatory system were detected. Aside from genes for the biosynthesis of amino acids, there is no common set of genes detected in these studies that would suggest a core genetic armamentarium that is required for host colonization or pathogenesis. The inability to identify a common set of virulence genes in these organisms has impeded the development of novel medical countermeasures. VIRULENCE DETERMINANTS Capsule Bacterial surfaces are commonly decorated with various polysaccharide structures, including lipopolysaccharide and capsule. These structures contribute to the pathogenesis of a number of bacterial pathogens. Subtractive hybridization was utilized to identify genetic loci within the B. mallei and B. psuedomallei genomes that are not present in the related, nonpathogenic B. thailandensis to identify genes that contribute to virulence. 23,24 Sequencing of these loci revealed the presence of genes involved in the biosynthesis, export, and translocation of capsular polysaccharide. Mutation of these genes in B. mallei results in strains that fail to react with polyclonal antisera raised against the B. pseudomallei capsule, suggesting that the capsules are structurally similar between the two species. B. mallei capsule mutants display significant attenuation in the Syrian hamster challenge model and the BALB/c aerosol challenge model. There was a greater than fold difference in lethal dose (LD) 50 between the wild-type and capsule mutants in the Syrian hamster model. There was a fold difference in LD 50 in the mouse model between the wild-type and mutant strains. Capsule mutants in B. pseudomallei display similar reductions in virulence (LD 50 of colony forming units [CFU]) in the mouse aerosol challenge model. Further, the addition of purified capsule increased the LD 50 (from to 34 CFU) of B. pseudomallei capsule mutants in the Syrian hamster. 25 These data suggest that the capsule is an essential virulence determinant in B. mallei and B. pseudomallei. Studies to determine the mechanistic contribution of the capsule to the virulence of B. pseudomallei have been performed. 25 The B. pseudomallei capsule was required for persistence in the blood as capsule-deficient mutants were recovered from the several organs of Syrian hamster at lower levels than wild type. Purified capsule restores the ability of acapsulated strains to survive in human serum. Western blot and immunofluorescence demonstrated that the deposition of complement factor C3b is enhanced in mutants, suggesting that the persistence of B. pseudomallei in blood is because of the prevention of opsonization by complement. Protein Secretion T3SS s are gram negative protein secretion systems, ancestrally related to flagella, capable of injecting protein substrates into the cytosol. Present in a number of plant and animal pathogens, T3SS s are critical for pathogenesis. Both B. mallei and B. pseudomallei encode a T3SS, which shares genetic similarity to T3SS s found in Salmonella and Shigella fl exneri. 26 Mutation analysis demonstrated that the T3SS is required for intracellular growth and phagosomal escape, suggesting that protein secretion through this system is critical to the pathogenesis of B. pseduomallei and mallei Mutants in the B. mallei T3SS are attenuated in the BALB/c mouse aerosol challenge model and the Syrian hamster intraperitoneal challenge model. 26 The role of specific secretion substrates of the Burkholderia T3SS has been investigated. BopE, a protein encoded within the Burkholderia T3SS loci, is secreted in a T3SS-dependent manner. Mutants in bope have reduced ability to invade nonphagocytic cells. BopE shares homology to SopE, a secreted T3SS effector protein involved in the uptake of S. typhimurium by nonphagocytic cells. 29 When expressed in eukaryotic cells, BopE induced cytoskeletal rearrangements. In vitro, BopE possess guanine nucleotide exchange activity for Cdc42 and Rac1, proteins involved in actin cytoskeleton regulation. 30 These data suggest that BopE is injected in T3SS-dependent mechanisms into cytosol of nonphagocytic eukaryotic cells where it induces the necessary cytoskeletal rearrangements to facilitate cellular invasion. Although this process is well studied in organisms such as Salmonella and Shigella, the characterization of a serected virulence factor in Burkholderia allows for mechanistic commonalities to be identified across these diverse bacterial pathogens. Mutation of a predicted structural component of the T3SS BipD results in significant attenuation following intraperitoneal or intranasal challenge in mice. 31 BipD shares homology with SipD, a T3SS protein in Salmonella that is required for the secretion of protein substrates. 32 The course of bacterial MILITARY MEDICINE, Vol. 174, June

4 replication in the liver and spleens on mice after challenge was markedly reduced in bipb mutants. These data implicate T3SS as a major contributor to the molecular pathogenesis of B. mallei and pseudomallei. B. pseudomallei and B. mallei are capable of intracellular survival and spread. To facilitate this process, B. pseudomallei and B. mallei utilize actin-based motility, a process that utilizes elements of the cellular cytoskeleton to propel the bacterium through the eukaryotic cell cytosol. Shigella fl exneri, Ricketsia rickettsii, and Listeria monocytogenes all possess cell surface proteins that facilitate this process and that nucleate and polymerize actin. 33 These proteins, known as autotransporters, are a class of bacterial proteins that mediate their own secretion and/or membrane localization. 34 A computational search of the B. pseudomallei genome revealed the presence of 11 predicted autosecreted proteins. 35 One of these proteins, designated BimA, possesses proline-rich region commonly found in proteins that stimulate actin polymerization. 36 Mutation of bima abolished the ability the B. pseudomallei to form membrane protrusions in vitro, suggesting a defect in actin-based motility. Inactivation of bima did not affect the function of the T3SS, as the bacteria retained the ability to escape from the phagosome. In vitro studies determined that BimA directly interacts with actin. 35 A series of cellular localization studies demonstrated that the actin-based motility involves only a subset of cellular proteins involved in intracellular spread of other bacterial pathogens, suggesting the molecular mechanism of intracellular spread employed by Burkholderia may differ from other bacterial species. 37 The in vivo contribution of bima to the pathogenesis of B. mallei was assessed.38 Mutation of bima did not affect virulence in the Syrian hamster, suggesting that cell-to-cell spread and actinbased motility may not be required for virulence. In 2007, Schell et al. reported the presence of a type VI secretion system (T6SS) in B. mallei. 38 T6SS is a newly identified family of gram negative protein secretion system that has been implicated in the pathogenesis of Vibrio cholerae and Pseudomonas aeruginosa. 39,40 Both B. mallei and B. pseudomallei contain additional genes that possess homology to T6SSs, suggesting there may be multiple T6SSs in pathogenic Burkholderia spp. SDS-PAGE and mass spectroscopy were used to identify proteins secreted into culture supernantants upon induction of protein secretion. A number of proteins were identified. One protein, Hcp1, was found to be secreted in a T6SS-dependent manner. Hcp1 and other T6SS genes are essential for full virulence in the Hamster model of infection. In these experiments, groups of five hamsters were challenged at increased doses ( CFU) with wild-type B. mallei or T6SS mutants. All hamsters challenged with CFU of wild-type B. mallei succumbed to infection. All of the hamsters challenged with the mutant strains survived. This suggests a critical role for the T6SS in B. mallei pathogenesis. 38 The identification of additional T6SS substrates and their respective role in host pathogen interactions will be essential to understanding the molecular mechanism of pathogenesis of these agents. Quorum Sensing A substantial number of bacterial species utilize a cell-density-dependent system of genetic regulation known as quorum sensing. These systems are based upon the production of N -acetyl homoserine lactones known as autoinducers. The LuxI protein is responsible for synthesis of the autoinducer. The LuxR family of proteins are transcriptional regulators that respond to sufficient concentrations of autoinducer. The amount of autoinducer present in the environment is dependent on the cell density of the bacteria. Quorum sensing systems induce or suppress the expression of multiple target genes and are involved in pathogenesis. A computational search of the B. mallei genome revealed the presence of two luxi and four luxr homologs. A search of the B. pseudomallei genome identified three luxi and five luxr homologs. Quorum sensing mutants of both B. mallei and pseudomallei were attenuated in the BALB/c mouse aerosol challenge model and the Syrian hamster intraperitoneal challenge model. 41,42 Significant increases in LD 50 s and increased survival rates and decreased organ colonization were exhibited by the quorum sensing mutants. The identity of genes regulated by the B. mallei and pseudomallei quorum sensing systems is unkown. An understanding of the contribution of these genes to pathogenesis will provide valuable information regarding the disease process. CONCLUSION Despite their recognition as category B bioterrorism agents by the CDC, many questions remain regarding the pathogenesis of B. pseudomallei and mallei. Basic mechanisms of pathogenesis, including the molecular mechanism responsible for intracellular survival and host immune modulation, need to be elucidated to produce therapeutic or preventative modalities. In particular, determining the correlates of protective, sterilizing immunity will be critical for vaccine development. B. pseudomallei and mallei appear to utilize multiple diverse mechanisms of protein secretion that are required for disease. An understanding of the mechanistic contributions of each secretion system to the disease processes is needed. A delineation of the role of quorum sensing in pathogenesis will allow for the identification of therapeutic interdiction points. At present, few antibiotics are FDA approved for the treatment or prophylaxis of glanders or melioidosis. A number of essential research questions need to be answered to inform the design of the next generation of medical countermeasures against these bacterial threat agents. REFERENCES 1. 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