Publications
42 results found
Wong ARC, Clements A, Raymond B, et al., 2012, The Interplay between the Escherichia coli Rho Guanine Nucleotide Exchange Factor Effectors and the Mammalian RhoGEF Inhibitor EspH, mBio, Vol: 3, ISSN: 2161-2129
Rho GTPases are important regulators of many cellular processes. Subversion of Rho GTPases is a common infection strategy employed by many important human pathogens. Enteropathogenic Escherichia coli and enterohemorrhagic Escherichia coli (EPEC and EHEC) translocate the effector EspH, which inactivates mammalian Rho guanine exchange factors (GEFs), as well as Map, EspT, and EspM2, which, by mimicking mammalian RhoGEFs, activate Rho GTPases. In this study we found that EspH induces focal adhesion disassembly, triggers cell detachment, activates caspase-3, and induces cytotoxicity. EspH-induced cell detachment and caspase-3 activation can be offset by EspT, EspM2, and the Salmonella Cdc42/Rac1 GEF effector SopE, which remain active in the presence of EspH. EPEC and EHEC therefore use a novel strategy of controlling Rho GTPase activity by translocating one effector to inactivate mammalian RhoGEFs, replacing them with bacterial RhoGEFs. This study also expands the functional range of bacterial RhoGEFs to include cell adhesion and survival.IMPORTANCE Many human pathogens use a type III secretion system to translocate effectors that can functionally be divided into signaling, disabling, and countervirulence effectors. Among the signaling effectors are those that activate Rho GTPases, which play a central role in coordinating actin dynamics. However, many pathogens also translocate effectors with antagonistic or counteractive functions. For example, Salmonella translocates SopE and SptP, which sequentially turn Rac1 and Cdc42 on and off. In this paper, we show that enteropathogenic E. coli translocates EspH, which inactivates mammalian RhoGEFs and triggers cytotoxicity and at the same time translocates the bacterial RhoGEFs EspM2 and EspT, which are insensitive to EspH, and so neutralizes EspH-induced focal adhesion disassembly, cell detachment, and caspase-3 activation. Our data point to an intriguing infection strategy in which EPEC and EHEC override cellular Rho GTPase
Clements A, Young JC, Constantinou N, et al., 2012, Infection strategies of enteric pathogenic <i>Escherichia coli</i>, GUT MICROBES, Vol: 3, Pages: 71-87, ISSN: 1949-0976
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- Citations: 190
Clements A, Smollett K, Lee SF, et al., 2011, EspG of enteropathogenic and enterohemorrhagic <i>E</i>. <i>coli</i> binds the Golgi matrix protein GM130 and disrupts the Golgi structure and function, CELLULAR MICROBIOLOGY, Vol: 13, Pages: 1429-1439, ISSN: 1462-5814
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- Citations: 30
Wilksch JJ, Yang J, Clements A, et al., 2011, MrkH, a novel c-di-GMP-dependent transcriptional activator, controls Klebsiella pneumoniae biofilm formation by regulating type 3 fimbriae expression, PLOS Pathogens, Vol: 7, ISSN: 1553-7366
Klebsiella pneumoniae causes significant morbidity and mortality worldwide, particularly amongst hospitalized individuals. The principle mechanism for pathogenesis in hospital environments involves the formation of biofilms, primarily on implanted medical devices. In this study, we constructed a transposon mutant library in a clinical isolate, K. pneumoniae AJ218, to identify the genes and pathways implicated in biofilm formation. Three mutants severely defective in biofilm formation contained insertions within the mrkABCDF genes encoding the main structural subunit and assembly machinery for type 3 fimbriae. Two other mutants carried insertions within the yfiN and mrkJ genes, which encode GGDEF domain- and EAL domain-containing c-di-GMP turnover enzymes, respectively. The remaining two isolates contained insertions that inactivated the mrkH and mrkI genes, which encode for novel proteins with a c-di-GMP-binding PilZ domain and a LuxR-type transcriptional regulator, respectively. Biochemical and functional assays indicated that the effects of these factors on biofilm formation accompany concomitant changes in type 3 fimbriae expression. We mapped the transcriptional start site of mrkA, demonstrated that MrkH directly activates transcription of the mrkA promoter and showed that MrkH binds strongly to the mrkA regulatory region only in the presence of c-di-GMP. Furthermore, a point mutation in the putative c-di-GMP-binding domain of MrkH completely abolished its function as a transcriptional activator. In vivo analysis of the yfiN and mrkJ genes strongly indicated their c-di-GMP-specific function as diguanylate cyclase and phosphodiesterase, respectively. In addition, in vitro assays showed that purified MrkJ protein has strong c-di-GMP phosphodiesterase activity. These results demonstrate for the first time that c-di-GMP can function as an effector to stimulate the activity of a transcriptional activator, and explain how type 3 fimbriae expression is coordinated with
Robinson KS, Clements A, Williams AC, et al., 2011, Bax Inhibitor 1 in apoptosis and disease, ONCOGENE, Vol: 30, Pages: 2391-2400, ISSN: 0950-9232
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- Citations: 61
Alcock F, Clements A, Webb C, et al., 2010, Tinkering Inside the Organelle, SCIENCE, Vol: 327, Pages: 649-650, ISSN: 0036-8075
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- Citations: 36
Clements A, Bursac D, Gatsos X, et al., 2009, The reducible complexity of a mitochondrial molecular machine, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 106, Pages: 15791-15795, ISSN: 0027-8424
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- Citations: 49
Clements A, Gaboriaud F, Duval JFL, et al., 2008, The major surface-associated saccharides of Klebsiella pneumoniae contribute to host cell association, PLOS One, Vol: 3, ISSN: 1932-6203
Analysing the pathogenic mechanisms of a bacterium requires an understanding of the composition of the bacterial cell surface. The bacterial surface provides the first barrier against innate immune mechanisms as well as mediating attachment to cells/surfaces to resist clearance. We utilised a series of Klebsiella pneumoniae mutants in which the two major polysaccharide layers, capsule and lipopolysaccharide (LPS), were absent or truncated, to investigate the ability of these layers to protect against innate immune mechanisms and to associate with eukaryotic cells. The capsule alone was found to be essential for resistance to complement mediated killing while both capsule and LPS were involved in cell-association, albeit through different mechanisms. The capsule impeded cell-association while the LPS saccharides increased cell-association in a non-specific manner. The electrohydrodynamic characteristics of the strains suggested the differing interaction of each bacterial strain with eukaryotic cells could be partly explained by the charge density displayed by the outermost polysaccharide layer. This highlights the importance of considering not only specific adhesin:ligand interactions commonly studied in adherence assays but also the initial non-specific interactions governed largely by the electrostatic interaction forces.
Clements A, Jenney AW, Farn JL, et al., 2008, Targeting subcapsular antigens for prevention of <i>Klebsiella pneumoniae</i> infections, VACCINE, Vol: 26, Pages: 5649-5653, ISSN: 0264-410X
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- Citations: 29
Clements A, Tull D, Jenney AW, et al., 2007, Secondary acylation of <i>Klebsiella pneumoniae</i> lipopolysaccharide contributes to sensitivity to antibacterial peptides, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 282, Pages: 15569-15577
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- Citations: 89
Carter DM, Miousse IR, Gagnon J-N, et al., 2006, Interactions between TonB from <i>Escherichia coli</i> and the periplasmic protein FhuD, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 281, Pages: 35413-35424
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- Citations: 41
Jenney AW, Clements A, Farn JL, et al., 2006, Seroepidemiology of <i>Klebsiella pneumoniae</i> in an Australian tertiary hospital and its implications for vaccine development, JOURNAL OF CLINICAL MICROBIOLOGY, Vol: 44, Pages: 102-107, ISSN: 0095-1137
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- Citations: 48
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