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Journal articleFairweather NF, Sekulovic1 O, Bedoya MO, et al., 2015,
The Clostridium difficile Cell Wall Protein CwpV Confers Phase-Variable Phage Resistance
, Molecular Microbiology, Vol: 98, Pages: 329-342, ISSN: 1365-2958Bacteriophages are present in virtually all ecosystems, and bacteria have developed multiple antiphage strategies to counter their attacks. Clostridium difficile is an important pathogen causing severe intestinal infections in humans and animals. Here we show that the conserved cell-surface protein CwpV provides antiphage protection in C. difficile. This protein, for which the expression is phase-variable, is classified into five types, each differing in their repeat-containing C-terminal domain. When expressed constitutively from a plasmid or the chromosome of locked ‘ON’ cells of C. difficile R20291, CwpV conferred antiphage protection. Differences in the level of phage protection were observed depending on the phage morphological group, siphophages being the most sensitive with efficiency of plaquing (EOP) values of < 5 × 10−7 for phages ϕCD38-2, ϕCD111 and ϕCD146. Protection against the myophages ϕMMP01 and ϕCD52 was weaker, with EOP values between 9.0 × 10−3 and 1.1 × 10−1. The C-terminal domain of CwpV carries the antiphage activity and its deletion, or part of it, significantly reduced the antiphage protection. CwpV does not affect phage adsorption, but phage DNA replication is prevented, suggesting a mechanism reminiscent of superinfection exclusion systems normally encoded on prophages. CwpV thus represents a novel ubiquitous host-encoded and phase-variable antiphage system in C. difficile.
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Conference paperPolo LM, Grundy G, Rulten S, et al., 2015,
New structural insights into PARP3 function
, 40th Congress of the Federation-of-European-Biochemical-Societies (FEBS) - The Biochemical Basis of Life, Publisher: WILEY-BLACKWELL, Pages: 397-397, ISSN: 1742-464X -
Journal articleWheat WH, Dhouib R, Angala SK, et al., 2015,
The presence of a galactosamine substituent on the arabinogalactan of <i>Mycobacterium tuberculosis</i> abrogates full maturation of human peripheral blood monocyte-derived dendritic cells and increases secretion of IL-10
, TUBERCULOSIS, Vol: 95, Pages: 476-489, ISSN: 1472-9792- Author Web Link
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- Citations: 10
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Journal articleLarrouy-Maumus GJ, 2015,
Cholesterol acquisition by Mycobacterium tuberculosis
, Virulence, ISSN: 2150-5608 -
Journal articleBouffartigues E, Moscoso JA, Duchesne R, et al., 2015,
The absence of the Pseudomonas aeruginosa OprF protein leads to increased biofilm formation through variation in c-di-GMP level
, Frontiers in Microbiology, Vol: 6, ISSN: 1664-302XOprF is the major outer membrane porin in bacteria belonging to the Pseudomonas genus. In previous studies, we have shown that OprF is required for full virulence expression of the opportunistic pathogen Pseudomonas aeruginosa. Here, we describe molecular insights on the nature of this relationship and report that the absence of OprF leads to increased biofilm formation and production of the Pel exopolysaccharide. Accordingly, the level of c-di-GMP, a key second messenger in biofilm control, is elevated in an oprF mutant. By decreasing c-di-GMP levels in this mutant, both biofilm formation and pel gene expression phenotypes were restored to wild-type levels. We further investigated the impact on two small RNAs, which are associated with the biofilm lifestyle, and found that expression of rsmZ but not of rsmY was increased in the oprF mutant and this occurs in a c-di-GMP-dependent manner. Finally, the extracytoplasmic function (ECF) sigma factors AlgU and SigX displayed higher activity levels in the oprF mutant. Two genes of the SigX regulon involved in c-di-GMP metabolism, PA1181 and adcA (PA4843), were up-regulated in the oprF mutant, partly explaining the increased c-di-GMP level. We hypothesized that the absence of OprF leads to a cell envelope stress that activates SigX and results in a c-di-GMP elevated level due to higher expression of adcA and PA1181. The c-di-GMP level can in turn stimulate Pel synthesis via increased rsmZ sRNA levels and pel mRNA, thus affecting Pel-dependent phenotypes such as cell aggregation and biofilm formation. This work highlights the connection between OprF and c-di-GMP regulatory networks, likely via SigX (ECF), on the regulation of biofilm phenotypes.
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Journal articleWilliams KJ, Jenkins VA, Barton GR, et al., 2015,
Deciphering the metabolic response of Mycobacterium tuberculosis to nitrogen stress.
, Molecular Microbiology, Vol: 97, Pages: 1142-1157, ISSN: 1365-2958A key component to the success of Mycobacterium tuberculosis as a pathogen is the ability to sense and adapt metabolically to the diverse range of conditions encountered in vivo, such as oxygen tension, environmental pH and nutrient availability. Although nitrogen is an essential nutrient for every organism, little is known about the genes and pathways responsible for nitrogen assimilation in M. tuberculosis. In this study we have used transcriptomics and ChIP-seq to address this. In response to nitrogen starvation a total of 185 genes were significantly differentially expressed (96 up-regulated and 89 down regulated; 5% genome) highlighting several significant areas of metabolic change during nitrogen limitation such as nitrate/nitrite metabolism, aspartate metabolism and changes in cell wall biosynthesis. We identify GlnR as a regulator involved in the nitrogen response, controlling the expression of at least 33 genes in response to nitrogen limitation. We identify a consensus GlnR binding site and relate its location to known transcriptional start sites. We also show that the GlnR response regulator plays a very different role in M. tuberculosis to that in non-pathogenic mycobacteria, controlling genes involved in nitric oxide detoxification and intracellular survival instead of genes involved in nitrogen scavenging.
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Journal articleFrankel GM, Habibzay M, Crepin-Sevenou V, et al., 2015,
Tir-induced actin remodeling triggers expression of CXCL1 in enterocytes and neutrophil recruitment during Citrobacter rodentium infection
, Infection and Immunity, Vol: 83, Pages: 3342-3354, ISSN: 1098-5522The hallmarks of enteropathogenic Escherichia coli (EPEC) infection are formation of attaching and effacing (A/E) lesions on mucosal surfaces and actin-rich pedestals on cultured cells, both dependent on the type III secretion system effector Tir. Following translocation into cultured cells and clustering by intimin, Tir Y474 is phosphorylated leading to recruitment of Nck, activation of N-WASP and actin polymerization via the Arp2/3 complex. A secondary, weak, actin polymerization pathway is triggered via an NPY motif (Y454). Importantly, Y454 and Y474 play no role in A/E lesion formation on mucosal surfaces following infection with the EPEC-like mouse pathogen Citrobacter rodentium. In this study we investigated the roles of Tir segments located upstream of Y451 and downstream of Y471 in C. rodentium colonization and A/E lesion formation. We also tested the role Tir residues Y451 and Y471 play in host immune responses to C. rodentium infection. We found that deletion of amino acids 382-462 or 478-547 had no impact on the ability of Tir to mediate A/E lesion formation, although deletion of amino acids 478-547 affected Tir translocation. Examination of enterocytes isolated from infected mice revealed that a C. rodentium expressing Tir_Y451A/Y471A recruited significantly less neutrophils to the colon and triggered less colonic hyperplasia on day 14 post infection, compared to infection with the wild type strain. Consistently, enterocytes isolated from mice infected with C. rodentium expressing Tir_Y451A/Y471A expressed significantly less CXCL1. These result show that Tir-induced actin remodeling plays a direct role in modulation of immune responses to C. rodentium infection.
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Journal articleMatthews SJ, Miliara X, Garnett J, et al., 2015,
Structural insight into the TRIAP1/PRELI-like domain family of mitochondrial phospholipid transfer complexes
, EMBO Reports, Vol: 16, Pages: 824-835, ISSN: 1469-221XThe composition of the mitochondrial membrane is important for its architecture and proper function. Mitochondria depend on a tightly regulated supply of phospholipid via intra-mitochondrial synthesis and by direct import from the endoplasmic reticulum. The Ups1/PRELI-like family together with its mitochondrial chaperones (TRIAP1/Mdm35) represent a unique heterodimeric lipid transfer system that is evolutionary conserved from yeast to man. Work presented here provides new atomic resolution insight into the function of a human member of this system. Crystal structures of free TRIAP1 and the TRIAP1–SLMO1 complex reveal how the PRELI domain is chaperoned during import into the intermembrane mitochondrial space. The structural resemblance of PRELI-like domain of SLMO1 with that of mammalian phoshatidylinositol transfer proteins (PITPs) suggest that they share similar lipid transfer mechanisms, in which access to a buried phospholipid-binding cavity is regulated by conformationally adaptable loops.
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Journal articleScanu T, Spaapen RM, Bakker JM, et al., 2015,
<i>Salmonella</i> Manipulation of Host Signaling Pathways Provokes Cellular Transformation Associated with Gallbladder Carcinoma
, CELL HOST & MICROBE, Vol: 17, Pages: 763-774, ISSN: 1931-3128- Author Web Link
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- Citations: 151
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Journal articleHengge R, Gruendling A, Jenal U, et al., 2015,
Bacterial signal transduction by cyclic Di-GMP and other nucleotide second messengers
, Journal of Bacteriology, Vol: 198, Pages: 15-26, ISSN: 1098-5530The first International Symposium on c-Di-GMP Signaling in Bacteria (22 to 25 March 2015, Harnack-Haus, Berlin, Germany) brought together 131 molecular microbiologists from 17 countries to discuss recent progress in our knowledge of bacterial nucleotide second messenger signaling. While the focus was on signal input, synthesis, degradation, and the striking diversity of the modes of action of the current second messenger paradigm, i.e., cyclic di-GMP (c-di-GMP), “classics” like cAMP and (p)ppGpp were also presented, in novel facets, and more recent “newcomers,” such as c-di-AMP and c-AMP-GMP, made an impressive appearance. A number of clear trends emerged during the 30 talks, on the 71 posters, and in the lively discussions, including (i) c-di-GMP control of the activities of various ATPases and phosphorylation cascades, (ii) extensive cross talk between c-di-GMP and other nucleotide second messenger signaling pathways, and (iii) a stunning number of novel effectors for nucleotide second messengers that surprisingly include some long-known master regulators of developmental pathways. Overall, the conference made it amply clear that second messenger signaling is currently one of the most dynamic fields within molecular microbiology, with major impacts in research fields ranging from human health to microbial ecology.
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