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  • Journal article
    Andreu N, Zelmer A, Sampson SL, Ikeh M, Bancroft GJ, Schaible UE, Wiles S, Robertson BDet al., 2013,

    Rapid in vivo assessment of drug efficacy against Mycobacterium tuberculosis using an improved firefly luciferase

    , Journal of Antimicrobial Chemotherapy, Vol: 68, Pages: 2118-2127, ISSN: 1460-2091

    Objectives In vivo experimentation is costly and time-consuming, and presents a major bottleneck in anti-tuberculosis drug development. Conventional methods rely on the enumeration of bacterial colonies, and it can take up to 4 weeks for Mycobacterium tuberculosis to grow on agar plates. Light produced by recombinant bacteria expressing luciferase enzymes can be used as a marker of bacterial load, and disease progression can be easily followed non-invasively in live animals by using the appropriate imaging equipment. The objective of this work was to develop a bioluminescence-based mouse model of tuberculosis to assess antibiotic efficacy against M. tuberculosis in vivo.Methods We used an M. tuberculosis strain carrying a red-shifted derivative of the firefly luciferase gene (FFlucRT) to infect mice, and monitored disease progression in living animals by bioluminescence imaging before and after treatment with the frontline anti-tuberculosis drug isoniazid. The resulting images were analysed and the bioluminescence was correlated with bacterial counts.Results Using bioluminescence imaging we detected as few as 1.7 × 103 and 7.5 × 104 reporter bacteria ex vivo and in vivo, respectively, in the lungs of mice. A good correlation was found between bioluminescence and bacterial load in both cases. Furthermore, a marked reduction in luminescence was observed in living mice given isoniazid treatment.Conclusions We have shown that an improved bioluminescent strain of M. tuberculosis can be visualized by non-invasive imaging in live mice during an acute, progressive infection and that this technique can be used to rapidly visualize and quantify the effect of antibiotic treatment. We believe that the model presented here will be of great benefit in early drug discovery as an easy and rapid way to identify active compounds in vivo.
  • Journal article
    Filloux A, 2013,

    MICROBIOLOGY A weapon for bacterial warfare

    , NATURE, Vol: 500, Pages: 284-285, ISSN: 0028-0836
  • Journal article
    Godfray HCJ, Donnelly CA, Kao RR, Macdonald W, McDonald RA, Petrokofsky G, Wood JLN, Woodroffe R, Young DB, McLean ARet al., 2013,

    A restatement of the natural science evidence base relevant to the control of bovine tuberculosis in Great Britain

    , Proceedings of the Royal Society B: Biological Sciences, Vol: 280, ISSN: 0962-8452

    Bovine tuberculosis (bTB) is a very important disease of cattle in Great Britain, where it has been increasing in incidence and geographical distribution. In addition to cattle, it infects other species of domestic and wild animals, in particular the European badger (Meles meles). Policy to control bTB is vigorously debated and contentious because of its implications for the livestock industry and because some policy options involve culling badgers, the most important wildlife reservoir. This paper describes a project to provide a succinct summary of the natural science evidence base relevant to the control of bTB, couched in terms that are as policy-neutral as possible. Each evidence statement is placed into one of four categories describing the nature of the underlying information. The evidence summary forms the appendix to this paper and an annotated bibliography is provided in the electronic supplementary material.
  • Journal article
    Corrigan RM, Gruendling A, 2013,

    Cyclic di-AMP: another second messenger enters the fray

    , NATURE REVIEWS MICROBIOLOGY, Vol: 11, Pages: 513-524, ISSN: 1740-1526
  • Journal article
    Collins JW, Meganck JA, Kuo C, Francis KP, Frankel Get al., 2013,

    4D Multimodality Imaging of Citrobacter rodentium Infections in Mice

    , JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, ISSN: 1940-087X
  • Journal article
    Raymond B, Young JC, Pallett M, Endres RG, Clements A, Frankel Get al., 2013,

    Subversion of trafficking, apoptosis, and innate immunity by type III secretion system effectors

    , TRENDS IN MICROBIOLOGY, Vol: 21, Pages: 430-439, ISSN: 0966-842X
  • Journal article
    Mikkelsen H, Hui K, Barraud N, Filloux Aet al., 2013,

    The pathogenicity island encoded PvrSR/RcsCB regulatory network controls biofilm formation and dispersal in Pseudomonas aeruginosa PA14

    , Molecular Microbiology, Vol: 89, Pages: 450-463, ISSN: 0950-382X

    Pseudomonas aeruginosa biofilm formation is linked to persistent infections in humans. Biofilm formation is facilitated by extracellular appendages, some of which are assembled by the Chaperone Usher Pathway (Cup). The cupD gene cluster is located on the PAPI‐1 pathogenicity island of strain PA14 and has probably been acquired together with four genes encoding two‐component signal transduction proteins. We have previously showed that the RcsB response regulator activates expression of the cupD genes, which leads to the production of CupD fimbriae and increased attachment. Here we show that RcsB activity is tightly modulated by two sensors, RcsC and PvrS. While PvrS acts as a kinase that enhances RcsB activity, RcsC has a dual function, first as a phosphorelay, and second as a phosphatase. We found that, under certain growth conditions, overexpression of RcsB readily induces biofilm dispersal. Microarray analysis shows that RcsB positively controls expression of pvrR that encodes the phosphodiesterase required for this dispersal process. Finally, in addition to the PAPI‐1 encoded cupD genes, RcsB controls several genes on the core genome, some of which encode orphan response regulators. We thus discovered that RcsB is central to a large regulatory network that fine‐tunes the switch between biofilm formation and dispersal.
  • Journal article
    Santos AJM, Meinecke M, Fessler MB, Holden DW, Boucrot Eet al., 2013,

    Preferential invasion of mitotic cells by Salmonella reveals that cell surface cholesterol is maximal during metaphase

    , JOURNAL OF CELL SCIENCE, Vol: 126, Pages: 2990-2996, ISSN: 0021-9533
  • Journal article
    Larrouy-Maumus G, Biswas T, Hunt DM, Kelly G, Tsodikov OV, de Carvalho LPSet al., 2013,

    Discovery of a glycerol 3-phosphate phosphatase reveals glycerophospholipid polar head recycling in Mycobacterium tuberculosis

    , PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: 11320-11325, ISSN: 0027-8424
  • Journal article
    Krishnan N, Robertson BD, Thwaites G, 2013,

    Pathways of IL-1β secretion by macrophages infected with clinical Mycobacterium tuberculosis strains

    , Tuberculosis, Vol: 93, Pages: 538-547, ISSN: 1873-281X

    The pro-inflammatory cytokine IL-1β is a key mediator of inflammation and plays an important role in the host resistance to Mycobacterium tuberculosis infections. To date, most studies have examined the mechanisms of IL-1β secretion using laboratory strains of M. tuberculosis and the findings may not be widely applicable to contemporary clinical strains. Here, we investigated the primary pathways of IL-1β secretion in macrophages infected with a panel of 17 clinical M. tuberculosis isolates, representing Euro-American, Indo-Oceanic and East-Asian/Beijing lineages. Our aim was to dissect the pathways involved in M. tuberculosis induced IL-1β secretion and to determine whether they are common to all clinical isolates. We found that the isolates were capable of eliciting variable concentrations of IL-1β from infected murine macrophages, but this phenomenon could not be attributed to differential IL-1β mRNA transcription or pro-IL-1β accumulation. We demonstrate that viable bacteria are required to induce IL-1β secretion from macrophages, but IL-1β secretion was only partially abrogated by caspase-1 inhibition. Almost complete IL-1β secretion inhibition was produced with combined caspase-1 and some serine protease inhibitors. Taken together, these findings demonstrate that clinical strains of M. tuberculosis employ a unique caspase-1 independent pathway to stimulate IL-1β secretion from macrophages.

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

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