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  • Journal article
    Rapun-Araiz B, Haag AF, De Cesare V, Gil C, Dorado-Morales P, Penades JR, Lasa Iet al., 2020,

    Systematic reconstruction of the complete two-component sensorial network in staphylococcus aureus.

    , mSystems, Vol: 5, Pages: 1-16, ISSN: 2379-5077

    In bacteria, adaptation to changes in the environment is mainly controlled through two-component signal transduction systems (TCSs). Most bacteria contain dozens of TCSs, each of them responsible for sensing a different range of signals and controlling the expression of a repertoire of target genes (regulon). Over the years, identification of the regulon controlled by each individual TCS in different bacteria has been a recurrent question. However, limitations associated with the classical approaches used have left our knowledge far from complete. In this report, using a pioneering approach in which a strain devoid of the complete nonessential TCS network was systematically complemented with the constitutively active form of each response regulator, we have reconstituted the regulon of each TCS of S. aureus in the absence of interference between members of the family. Transcriptome sequencing (RNA-Seq) and proteomics allowed us to determine the size, complexity, and insulation of each regulon and to identify the genes regulated exclusively by one or many TCSs. This gain-of-function strategy provides the first description of the complete TCS regulon in a living cell, which we expect will be useful to understand the pathobiology of this important pathogen.IMPORTANCE Bacteria are able to sense environmental conditions and respond accordingly. Their sensorial system relies on pairs of sensory and regulatory proteins, known as two-component systems (TCSs). The majority of bacteria contain dozens of TCSs, each of them responsible for sensing and responding to a different range of signals. Traditionally, the function of each TCS has been determined by analyzing the changes in gene expression caused by the absence of individual TCSs. Here, we used a bacterial strain deprived of the complete TC sensorial system to introduce, one by one, the active form of every TCS. This gain-of-function strategy allowed us to identify the changes in gene expression conferred by each TCS wit
  • Journal article
    Vincent CM, Dionne MS, 2020,

    Disparate regulation of <i>imd</i> drives sex differences in infection pathology in <i>Drosophila melanogaster</i>

    <jats:title>Abstract</jats:title><jats:p>Male and female animals exhibit differences in infection outcomes. One possible source of sexually dimorphic immunity is sex-specific costs of immune activity or pathology, but little is known about the independent effects of immune-induced versus microbe-induced pathology, and whether these may differ for the sexes. Here, through measuring metabolic and physiological outputs in wild-type and immune-compromised <jats:italic>Drosophila melanogaster</jats:italic>, we test whether the sexes are differentially impacted by these various sources of pathology and identify a critical regulator of this difference. We find that the sexes exhibit differential immune activity but similar bacteria-derived metabolic pathology. We show that female-specific immune-inducible expression of <jats:italic>PGRP-LB</jats:italic>, a negative regulator of the Imd pathway, enables females to reduce immune activity in response to reductions in bacterial numbers. In the absence of <jats:italic>PGRP-LB</jats:italic>, females are more resistant of infection, confirming the functional importance of this regulation and suggesting that female-biased immune restriction comes at a cost.</jats:p>
  • Journal article
    Fisch D, Clough B, Domart M-C, Encheva V, Bando H, Snijders AP, Collinson LM, Yamamoto M, Shenoy AR, Frickel E-Met al., 2020,

    Human GBP1 differentially targets salmonella and toxoplasma to license recognition of microbial ligands and caspase-mediated death

    , Cell Reports, Vol: 32, Pages: 1-22, ISSN: 2211-1247

    Interferon-inducible guanylate-binding proteins (GBPs) promote cell-intrinsic defense through host cell death. GBPs target pathogens and pathogen-containing vacuoles and promote membrane disruption for release of microbial molecules that activate inflammasomes. GBP1 mediates pyroptosis or atypical apoptosis of Salmonella Typhimurium (STm)- or Toxoplasma gondii (Tg)- infected human macrophages, respectively. The pathogen-proximal detection-mechanisms of GBP1 remain poorly understood, as humans lack functional immunity-related GTPases (IRGs) that assist murine Gbps. Here, we establish that GBP1 promotes the lysis of Tg-containing vacuoles and parasite plasma membranes, releasing Tg-DNA. In contrast, we show GBP1 targets cytosolic STm and recruits caspase-4 to the bacterial surface for its activation by lipopolysaccharide (LPS), but does not contribute to bacterial vacuole escape. Caspase-1 cleaves and inactivates GBP1, and a cleavage-deficient GBP1D192E mutant increases caspase-4-driven pyroptosis due to the absence of feedback inhibition. Our studies elucidate microbe-specific roles of GBP1 in infection detection and its triggering of the assembly of divergent caspase signaling platforms.
  • Journal article
    Ritchie AI, Singanayagam A, 2020,

    Metagenomic Characterization of the Respiratory Microbiome A Piece de Resistance

    , AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 202, Pages: 321-322, ISSN: 1073-449X
  • Journal article
    Vakili M, Aliyali M, Mortezaee V, Mahdaviani SA, Poorabdollah M, Mirenayat MS, Fakharian A, Hassanzad M, Abastabar M, Charati JY, Haghani I, Tavakoli M, Maleki M, Armstrong-James D, Hedayati MTet al., 2020,

    Relationship between spirometry results and colonisation of <i>Aspergillus</i> species in allergic asthma

    , CLINICAL RESPIRATORY JOURNAL, Vol: 14, Pages: 748-757, ISSN: 1752-6981
  • Journal article
    Ding NS, McDonald JAK, Perdones-Montero A, Rees DN, Adegbola SO, Misra R, Hendy P, Penez L, Marchesi JR, Holmes E, Sarafian MH, Hart ALet al., 2020,

    Metabonomics and the Gut Microbiome Associated With Primary Response to Anti-TNF Therapy in Crohn's Disease

    , JOURNAL OF CROHNS & COLITIS, Vol: 14, Pages: 1090-1102, ISSN: 1873-9946
  • Journal article
    Pataia V, McIlvride S, Papacleovoulou G, Ovadia C, McDonald JAK, Wahlstrom A, Jansen E, Adorini L, Shapiro D, Marchesi JR, Marschall H-U, Williamson Cet al., 2020,

    Obeticholic acid improves fetal bile acid profile in a mouse model of gestational hypercholanemia

    , AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, Vol: 319, Pages: G197-G211, ISSN: 0193-1857
  • Journal article
    Murphy P, Xu Y, Rouse SL, Jaffray EG, Plechanovova A, Matthews SJ, Carlos Penedo J, Hay RTet al., 2020,

    Functional 3D architecture in an intrinsically disordered E3 ligase domain facilitates ubiquitin transfer

    , NATURE COMMUNICATIONS, Vol: 11, ISSN: 2041-1723
  • Journal article
    Currie AJ, Main ET, Wilson HM, Armstrong-James D, Warris Aet al., 2020,

    CFTR Modulators Dampen<i>Aspergillus</i>-Induced Reactive Oxygen Species Production by Cystic Fibrosis Phagocytes

    , FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, Vol: 10, ISSN: 2235-2988
  • Journal article
    Yi L, Rebollo-Ramirez S, Larrouy-Maumus G, 2020,

    Metabolomics reveals that the cAMP receptor protein regulates nitrogen and peptidoglycan synthesis in Mycobacterium tuberculosis

    , RSC Advances: an international journal to further the chemical sciences, Vol: 10, Pages: 26212-26219, ISSN: 2046-2069

    Mycobacterium tuberculosis requires extensive sensing and response to environment for its successful survival and pathogenesis, and signalling by cyclic adenosine 3′,5′-monophosphate (cAMP) is an important mechanism. cAMP regulates expression of target genes via interaction with downstream proteins, one of which is cAMP receptor protein (CRP), a global transcriptional regulator. Previous genomic works had identified regulon of CRP and investigated transcriptional changes in crp deletion mutant, however a link to downstream metabolomic events were lacking, which would help better understand roles of CRP. This work aims at investigating changes at metabolome level in M. tuberculosis crp deletion mutant combining untargeted LC-MS analysis and 13C isotope tracing analysis. The results were compared with previously published RNA sequencing data. We identified increasing abundances of metabolites related to nitrogen metabolism including ornithine, citrulline and glutamate derivatives, while 13C isotope labelling analysis further showed changes in turnover of these metabolites and amino acids, suggesting regulatory roles of CRP in nitrogen metabolism. Upregulation of diaminopimelic acid and its related genes also suggested role of CRP in regulation of peptidoglycan synthesis. This study provides insights on metabolomic aspects of cAMP-CRP regulatory pathway in M. tuberculosis and links to previously published transcriptomic data drawing a more complete map.

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