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  • Journal article
    Grundling A, Lee V, 2016,

    Old concepts, new molecules and current approaches applied to the bacterial nucleotide signalling field

    , Philosophical Transactions of the Royal Society B: Biological Sciences, Vol: 371, ISSN: 1471-2970

    Signalling nucleotides are key molecules that help bacteria to rapidly coordinate cellular pathways and adaptto changes in their environment. During the past ten years, the nucleotide-signalling field has seen muchexcitement, as several new signalling nucleotides have been discovered in both eukaryotic and bacterial cells.The fields have since advanced quickly, aided by the development of important tools such as the synthesis ofmodified nucleotides, which combined with sensitive mass spectrometry methods, allowed for the rapididentification of specific receptor proteins along with other novel genome-wide screening methods. In thisreview, we will describe the principle concepts of nucleotide signalling networks and summarize the recentwork that led to the discovery of the novel signalling nucleotides. We will also highlight current approachesapplied to the research in the field as well as resources and methodological advances aiding in a rapididentification of nucleotide specific receptor proteins.

  • Journal article
    Crepin VF, Collins JW, Habibzay M, Frankel Get al., 2016,

    Citrobacter rodentium mouse model of bacterial infection.

    , Nature Protocols, Vol: 11, Pages: 1851-1876, ISSN: 1754-2189

    Infection of mice with Citrobacter rodentium is a robust model to study bacterial pathogenesis, mucosal immunology, the health benefits of probiotics and the role of the microbiota during infection. C. rodentium was first isolated by Barthold from an outbreak of mouse diarrhea in Yale University in 1972 and was 'rediscovered' by Falkow and Schauer in 1993. Since then the use of the model has proliferated, and it is now the gold standard for studying virulence of the closely related human pathogens enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC, respectively). Here we provide a detailed protocol for various applications of the model, including bacterial growth, site-directed mutagenesis, mouse inoculation (from cultured cells and after cohabitation), monitoring of bacterial colonization, tissue extraction and analysis, immune responses, probiotic treatment and microbiota analysis. The main protocol, from mouse infection to clearance and analysis of tissues and host responses, takes ∼5 weeks to complete.

  • Journal article
    Esmail H, Lai RP, Lesosky M, Wilkinson KA, Graham CM, Coussens AK, Oni T, Warwick JM, Said-Hartley Q, Koegelenberg CF, Walzl G, Flynn JL, Young DB, Barry Iii CE, O'Garra A, Wilkinson RJet al., 2016,

    Characterization of progressive HIV-associated tuberculosis using 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission and computed tomography

    , Nature Medicine, Vol: 22, ISSN: 1546-170X

    Tuberculosis is classically divided into states of latent infection and active disease. Using combined positron emission and computed tomography in 35 asymptomatic, antiretroviral-therapy-naive, HIV-1-infected adults with latent tuberculosis, we identified ten individuals with pulmonary abnormalities suggestive of subclinical, active disease who were substantially more likely to progress to clinical disease. Our findings challenge the conventional two-state paradigm and may aid future identification of biomarkers that are predictive of progression.

  • Journal article
    Wilkinson RJ, Esmail H, Lesosky M, Lai RP, Wilkinson KA, Graham CM, Coussens AK, Oni T, Warwick J, Said-Hartley Q, Koegenelburg CF, Walzl G, Flynn JL, young DB, Barry CE, O'Garra Aet al.,

    [18F]-FDG PET/CT characterisation of progressive HIV-associated tuberculosis

    , Nature Medicine, ISSN: 1546-170X

    Tuberculosis is classically divided into states of latent infection and active disease. Usingcombined positron emission and computed tomography in 35 asymptomatic, antiretroviraltherapy naïve, HIV-1 infected adults with latent tuberculosis, we identified ten individualswith pulmonary abnormalities suggestive of subclinical, active disease who weresignificantly more likely to progress to clinical disease. Our findings challenge theconventional two-state paradigm and may aid future identification of biomarkers predictiveof progression.

  • Journal article
    Grundy GJ, Polo LM, Zeng Z, Rulten SL, Hoch NC, Paomephan P, Xu Y, Sweet SM, Thorne AW, Oliver AW, Matthews SJ, Pearl LH, Caldecott KWet al., 2016,

    PARP3 is a sensor of nicked nucleosomes and monoribosylates histone H2B(Glu2).

    , Nature Communications, Vol: 7, ISSN: 2041-1723

    PARP3 is a member of the ADP-ribosyl transferase superfamily that we show accelerates the repair of chromosomal DNA single-strand breaks in avian DT40 cells. Two-dimensional nuclear magnetic resonance experiments reveal that PARP3 employs a conserved DNA-binding interface to detect and stably bind DNA breaks and to accumulate at sites of chromosome damage. PARP3 preferentially binds to and is activated by mononucleosomes containing nicked DNA and which target PARP3 trans-ribosylation activity to a single-histone substrate. Although nicks in naked DNA stimulate PARP3 autoribosylation, nicks in mononucleosomes promote the trans-ribosylation of histone H2B specifically at Glu2. These data identify PARP3 as a molecular sensor of nicked nucleosomes and demonstrate, for the first time, the ribosylation of chromatin at a site-specific DNA single-strand break.

  • Journal article
    Schuster C, Bellows L, Tosi T, Campeotto, Corrigan, Freemont P, Grundling Aet al., 2016,

    The second messenger c-di-AMP inhibits the osmolyte uptake system OpuC in Staphylococcus aureus

    , Science Signaling, Vol: 9, Pages: ra81-ra81, ISSN: 1945-0877

    Staphylococcus aureus is an important opportunistic human pathogen that is highly resistant to osmotic stresses. To survive an increase in osmolarity, bacteria immediately take up potassium ions and small organic compounds known as compatible solutes. The second messenger cyclic diadenosine monophosphate (c-di-AMP) reduces the ability of bacteria to withstand osmotic stress by binding to and inhibiting several proteins that promote potassium uptake. We identified OpuCA, the adenosine triphosphatase (ATPase) component of an uptake system for the compatible solute carnitine, as a c-di-AMP target protein in S. aureus and found that the LAC*ΔgdpP strain of S. aureus, which overproduces c-di-AMP, showed reduced carnitine uptake. The paired cystathionine-β-synthase (CBS) domains of OpuCA bound to c-di-AMP, and a crystal structure revealed a putative binding pocket for c-di-AMP in the cleft between the two CBS domains. Thus, c-di-AMP inhibits osmoprotection through multiple mechanisms.

  • Journal article
    Brown RL, Clarke TB, 2016,

    The regulation of host defences to infection by the microbiota

    , Immunology, Vol: 150, Pages: 1-6, ISSN: 0019-2805

    The skin and mucosal epithelia of humans and other mammals are permanently colonised by large microbial communities (the microbiota). Due to this life-long association with the microbiota, these microbes have an extensive influence over the physiology of their host organism. It is now becoming apparent that nearly all tissues and organ systems, whether in direct contact with the microbiota, or in deeper host sites, are under microbial influence. The immune system is perhaps the most profoundly affected, with the microbiota programming both its innate and adaptive arms. The regulation of immunity by the microbiota helps protect the host against intestinal and extra-intestinal infection by many classes of pathogen. In this review, we will discuss the experimental evidence supporting a role for the microbiota in regulating host defences to extra-intestinal infection, draw together common mechanistic themes, including the central role of pattern recognition receptors, and outline outstanding questions which need to be answered. This article is protected by copyright. All rights reserved.

  • Journal article
    Baek K, Bowman L, Millership C, Dupont Sogaard M, Kaever V, Savijoki K, Varmanen P, Nyman T, Grundling A, Frees Det al., 2016,

    The cell wall polymer lipoteichoic acid becomes non-essential in Staphylococcus aureus cells lacking the ClpX chaperone

    , mBio, Vol: 7, ISSN: 2150-7511

    Lipoteichoic acid is an essential component of the Staphylococcus aureus cell envelope and an attractive target for the development of vaccines and antimicrobials directed against antibiotic-resistant Gram-positive bacteria such as methicillin-resistant S. aureus and vancomycin-resistant enterococci. In this study, we showed that the lipoteichoic acid polymer is essential for growth of S. aureus only as long as the ClpX chaperone is present in the cell. Our results indicate that lipoteichoic acid and ClpX play opposite roles in a pathway that controls two key cell division processes in S. aureus, namely, septum formation and autolytic activity. The discovery of a novel functional connection in the genetic network that controls cell division in S. aureus may expand the repertoire of possible strategies to identify compounds or compound combinations that kill antibiotic-resistant S. aureus.

  • Journal article
    Brown DR, Sheppard CM, Matthews S, Wigneshweraraj Set al., 2016,

    The Xp10 bacteriophage protein P7 inhibits transcription by the major and major variant forms of the host RNA polymerase via a common mechanism

    , Journal of Molecular Biology, Vol: 428, Pages: 3911-3919, ISSN: 1089-8638

    The σ factor is a functionally obligatory subunit of the bacterial transcription machinery, the RNA polymerase. Bacteriophage-encoded small proteins that either modulate or inhibit the bacterial RNAP to allow the temporal regulation of bacteriophage gene expression often target the activity of the major bacterial σ factor, σ70. Previously, we showed that during Xanthomonas oryzae phage Xp10 infection, the phage protein P7 inhibits the host RNAP by preventing the productive engagement with the promoter and simultaneously displaces the σ70 factor from the RNAP. In this study, we demonstrate that P7 also inhibits the productive engagement of the bacterial RNAP containing the major variant bacterial σ factor, σ54, with its cognate promoter. The results suggest for the first time that the major variant form of the host RNAP can also be targeted by bacteriophage-encoded transcription regulatory proteins. Since the major and major variant σ factor interacting surfaces in the RNAP substantially overlap, but different regions of σ70 and σ54 are used for binding to the RNAP, our results further underscore the importance of the σ–RNAP interface in bacterial RNAP function and regulation and potentially for intervention by antibacterials.

  • Journal article
    Liang X, Liu B, Zhu F, Scannapieco FA, Haase EM, Matthews S, Wu Het al., 2016,

    A distinct sortase SrtB anchors and processes a streptococcal adhesin AbpA with a novel structural property.

    , Scientific Reports, Vol: 6, ISSN: 2045-2322

    Surface display of proteins by sortases in Gram-positive bacteria is crucial for bacterial fitness and virulence. We found a unique gene locus encoding an amylase-binding adhesin AbpA and a sortase B in oral streptococci. AbpA possesses a new distinct C-terminal cell wall sorting signal. We demonstrated that this C-terminal motif is required for anchoring AbpA to cell wall. In vitro and in vivo studies revealed that SrtB has dual functions, anchoring AbpA to the cell wall and processing AbpA into a ladder profile. Solution structure of AbpA determined by NMR reveals a novel structure comprising a small globular α/β domain and an extended coiled-coil heliacal domain. Structural and biochemical studies identified key residues that are crucial for amylase binding. Taken together, our studies document a unique sortase/adhesion substrate system in streptococci adapted to the oral environment rich in salivary amylase.

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