Ricky L. Ulrich

Institute for Learning Innovation

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David DeShazer

United States Army Medical Research Institute of Infectious Diseases

Rekha G. Panchal

Pasteur Hellenic Institute

Douglas Lane

United States Army Medical Research Institute of Infectious Diseases

Sina Bavari

United States Army Medical Research Institute of Infectious Diseases

Melanie Ulrich

Louisiana State University

Tara Kenny

AstraZeneca (United States)

Brett Eaton

National Institute of Allergy and Infectious Diseases

William C. Nierman

J. Craig Venter Institute

Jenifer F. Ojeda

United States Army Medical Research Institute of Infectious Diseases

Sun Kim

Korea University

Cooperative Institutions

United States Army Medical Research Institute of Infectious Diseases

National Institutes of Health

J. Craig Venter Institute

National Institute of Allergy and Infectious Diseases

University of Maryland, Baltimore

George Washington University

United States Department of the Army

Johns Hopkins University

National Cancer Institute

Biotechnology Institute

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Structural flexibility in the Burkholderia mallei genome

Proceedings of the National Academy of Sciences (2004)

William C. Nierman David DeShazer Sun Kim Hervé Tettelin William Nelson

The complete genome sequence of Burkholderia mallei ATCC 23344 provides insight into this highly infectious bacterium's pathogenicity and evolutionary history. B. mallei , the etiologic agent of glanders, has come under renewed scientific investigation as a result of recent concerns about its past and potential future use as a biological weapon. Genome analysis identified a number of putative virulence factors whose function was supported by comparative genome hybridization and expression profiling of the bacterium in hamster liver in vivo . The genome contains numerous insertion sequence elements that have mediated extensive deletions and rearrangements of the genome relative to Burkholderia pseudomallei . The genome also contains a vast number (>12,000) of simple sequence repeats. Variation in simple sequence repeats in key genes can provide a mechanism for generating antigenic variation that may account for the mammalian host's inability to mount a durable adaptive immune response to a B. mallei infection.

Comparative Genomics

Antigenic variation

10.1073/pnas.0403306101

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Virulence and Cellular Interactions of Burkholderia multivorans in Chronic Granulomatous Disease

Infection and Immunity (2009)

Adrian M. Zelazny Li Ding Houda Zghal Elloumi Lauren R. Brinster Fran Benedetti

ABSTRACT Chronic granulomatous disease (CGD) patients are susceptible to life-threatening infections by the Burkholderia cepacia complex. We used leukocytes from CGD and healthy donors and compared cell association, invasion, and cytokine induction by Burkholderia multivorans strains. A CGD isolate, CGD1, showed higher cell association than that of an environmental isolate, Env1, which correlated with cell entry. All B. multivorans strains associated significantly more with cells from CGD patients than with those from healthy donors. Similar findings were observed with another CGD pathogen, Serratia marcescens , but not with Escherichia coli . In a mouse model of CGD, strain CGD1 was virulent while Env1 was avirulent. B. multivorans organisms were found in the spleens of CGD1-infected mice at levels that were 1,000 times higher than those found in Env1-infected mice, which was coincident with higher levels of the proinflammatory cytokine interleukin-1β. Taken together, these results may shed light on the unique susceptibility of CGD patients to specific pathogens.

Chronic Granulomatous Disease

Burkholderia cepacia complex

Proinflammatory cytokine

Serratia

10.1128/iai.00259-09

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Quorum Sensing: A transcriptional Regulatory System Involved in the Pathogenicity of Burkholderia mallei

Ricky L. Ulrich David DeShazer Harry B. Hines Jeffrey A. Jeddeloh

Numerous gram-negative bacterial pathogens regulate virulence factor expression by using a cell density mechanism termed quorum sensing (QS).An in silico analysis of the Burkholderia mallei ATCC 23344 genome revealed that it encodes at least two luxI and four luxR homologues.Using mass spectrometry, we showed that wild-type B. mallei produces the signaling molecules N-octanoyl-homoserine lactone and N-decanoyl-homoserine lactone.To determine if QS is involved in the virulence of B. mallei, we generated mutations in each putative luxIR homologue and tested the pathogenicities of the derivative strains in aerosol BALB/c mouse and intraperitoneal hamster models.Disruption of the B. mallei QS alleles, especially in RJ16 (bmaII) and RJ17 (bmaI3), which are luxI mutants, significantly reduced virulence, as indicated by the survival of mice who were aerosolized with 10 4 CFU (10 50% lethal doses [LD 50 s]).For the B. mallei transcriptional regulator mutants (luxR homologues), mutation of the bmaR5 allele resulted in the most pronounced decrease in virulence, with 100% of the challenged animals surviving a dose of 10 LD 50 s.Using a Syrian hamster intraperitoneal model of infection, we determined the LD 50 s for wild-type B. mallei and each QS mutant.An increase in the relative LD 50 was found for RJ16 (bmaI1) (>967 CFU), RJ17 (bmaI3) (115 CFU), and RJ20 (bmaR5) (151 CFU) compared to wild-type B. mallei (<13 CFU).These findings demonstrate that B. mallei carries multiple luxIR homologues that either directly or indirectly regulate the biosynthesis of an essential virulence factor(s) that contributes to the pathogenicity of B. mallei in vivo.

Pathogenicity island

10.21236/ada429432

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The Early Stage of Bacterial Genome-Reductive Evolution in the Host

SciVee (2010)

Song Han Junghyun Hwang Hyojeong Yi Ricky L. Ulrich Yan Yu

10.4016/18488.01

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Additional file 7: Table S4. of Characterization of the murine macrophage response to infection with virulent and avirulent Burkholderia species

Figshare (2015)

Chih-Yuan Chiang Ricky L. Ulrich Melanie Ulrich Brett Eaton Jenifer F. Ojeda

UCC nomenclature for the different Burkholderia spp. Explanation of the column headings: Burkholderia Species: names of the species used in this study; Strain names: names of the strains; UCC nomenclature: the corresponding nomenclature used within USAMRIID. (XLSX 10 kb)

Table (database)

10.6084/m9.figshare.c.3616265_d5

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The Burkholderia mallei BmaR3-BmaI3 Quorum-Sensing System Produces and Responds to N -3-Hydroxy-Octanoyl Homoserine Lactone

Journal of Bacteriology (2008)

Breck A. Duerkop Jake P. Herman Ricky L. Ulrich Mair E. A. Churchill E. Peter Greenberg

Burkholderia mallei has two acyl-homoserine lactone (acyl-HSL) signal generator-receptor pairs and two additional signal receptors, all of which contribute to virulence. We show that B. mallei produces N-3-hydroxy-octanoyl HSL (3OHC8-HSL) but a bmaI3 mutant does not. Recombinant Escherichia coli expressing BmaI3 produces hydroxylated acyl-HSLs, with 3OHC8-HSL being the most abundant compound. In recombinant E. coli, BmaR3 responds to 3OHC8-HSL but not to other acyl-HSLs. These data indicate that the signal for BmaR3-BmaI3 quorum sensing is 3OHC8-HSL.

Homoserine

10.1128/jb.00246-08

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Quorum Quenching: Enzymatic Disruption of N-Acylhomoserine Lactone-Mediated Bacterial Communication in Burkholderia thailandensis

Ricky L. Ulrich

Many species of gram-negative bacteria communicate by synthesizing, secreting, and responding to Nacylhomoserine lactones (AHLs), a mechanism termed quorum sensing.Several investigations have characterized numerous AHL-degrading enzymes (AiiA lactonases) encoded by environmental isolates of Bacillus spp.The Burkholderia thailandensis quorum system is comprised of at least three AHL synthases (AHSs) and five transcriptional regulators belonging to the LuxIR class of proteins.Expression of the Bacillus anthracis (Ames strain) AiiA lactonase in B. thailandensis completely abolished the accumulation of N-decanoylhomoserine lactone (C 10 -HSL) and N-octanoylhomoserine lactone (C 8 -HSL), reduced N-hexanoylhomoserine lactone (C 6 -HSL) levels, altered both swarming and twitching motility, caused a significant increase in generation time, and affected carbon metabolism.In contrast, heterologous expression of the Bacillus cereus strain A24 AiiA lactonase in B. thailandensis reduced the concentrations of C 6 -HSL, C 8 -HSL, and C 10 -HSL to nondetectable levels; altered both swarming and twitching motility; and caused fluctuations in carbon utilization.Individual disruption of the B. thailandensis AHSs, specifically disruption of the btaI1 and btaI3 genes, which encode the proteins that direct the synthesis of C 8 -HSL and C 6 -HSL, respectively, caused the hyper-beta-hemolysis of sheep erythrocytes on blood agar plates.In contrast, AHL cleavage in B. thailandensis by the Bacillus AiiA lactonases failed to enhance beta-hemolytic activity.The results of this study demonstrate that heterologous expression of Bacillus sp.AiiA lactonases in B. thailandensis reduced AHL accumulation, affected both swarming and twitching motility, increased generation time, altered substrate utilization, and prevented the betahemolysis of sheep erythrocytes.

Quorum Quenching

10.21236/ada428608

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Citations (7)

Development of a polymerase chain reaction assay for the specific identification of Burkholderia mallei and differentiation from Burkholderia pseudomallei and other closely related Burkholderiaceae

Diagnostic Microbiology and Infectious Disease (2006)

Ricky L. Ulrich Melanie Ulrich Mark A. Schell Sun Kim David DeShazer

Burkholderia pseudomallei

Melioidosis

10.1016/j.diagmicrobio.2005.11.007

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Type VI secretion is a major virulence determinant in Burkholderia mallei

Molecular Microbiology (2007)

Mark A. Schell Ricky L. Ulrich Wilson J. Ribot Ernst E. Brueggemann Harry B. Hines

Summary Burkholderia mallei is a host‐adapted pathogen and a category B biothreat agent. Although the B. mallei VirAG two‐component regulatory system is required for virulence in hamsters, the virulence genes it regulates are unknown. Here we show with expression profiling that overexpression of virAG resulted in transcriptional activation of ∼60 genes, including some involved in capsule production, actin‐based intracellular motility, and type VI secretion (T6S). The 15 genes encoding the major sugar component of the homopolymeric capsule were up‐expressed > 2.5‐fold, but capsule was still produced in the absence of virAG . Actin tail formation required virAG as well as bimB , bimC and bimE , three previously uncharacterized genes that were activated four‐ to 15‐fold when VirAG was overproduced. Surprisingly, actin polymerization was found to be dispensable for virulence in hamsters. In contrast, genes encoding a T6S system were up‐expressed as much as 30‐fold and mutations in this T6S gene cluster resulted in strains that were avirulent in hamsters. SDS‐PAGE and mass spectrometry demonstrated that BMAA0742 was secreted by the T6S system when virAG was overexpressed. Purified His‐tagged BMAA0742 was recognized by glanders antiserum from a horse, a human and mice, indicating that this Hcp‐family protein is produced in vivo during infection.

Gene cluster

10.1111/j.1365-2958.2007.05734.x

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Citations (313)

Reduced expression of CD45 Protein-Tyrosine Phosphatase Pr

Rekha G. Panchal Ricky L. Ulrich Steven B. Bradfute Douglas Lane Gordon Ruthel

Abstract : The modulation of cellular processes by small molecule inhibitors, gene inactivation or targeted knock-down approaches combined with phenotypic screens are powerful approaches to delineate complex cellular pathways and to identify key players involved in disease pathogenesis. Using chemical genetic screening, we tested a library of known phosphatase inhibitors and identified several compounds that protected Bacillus anthracis infected macrophages from cell death. The most potent compound was assayed against a panel of sixteen different phosphatases of which CD45 was found to be most sensitive to inhibition. Testing of a known CD45 inhibitor also protected B. anthracis infected macrophages from cell death. Subsequently, in vivo studies were conducted with both gene targeted knock down of CD45 and genetically engineered mice expressing reduced levels of CD45. Under both conditions, mice were protected following infection with the virulent Ames B. anthracis. In contrast, wild type mice, mice with disrupted CD45 phosphatase activity and CD45 knockout mice succumbed to these pathogens. Mechanism-based studies suggest that the protection provided by reduced CD45 levels resulted from dynamic host immunity via accelerated immune cell homeostasis that may diminish the impact of apoptosis during the infection. An important implication of this study is that compounds identified based on their ability to produce specific cellular phenotypes can be valuable research tools. Furthermore, if the therapeutic class of the compound is known, the typically arduous challenge of molecular target identification is significantly more efficient.

Bacillus anthracis

Knockout mouse

Phenotypic screening

Gene knockout

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