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51. Natural variation in the parameters of innate immune cells is preferentially driven by genetic factors

Author

Petar Scepanovic, Julie Hunkapiller, Jacob Bergstedt, Alejandra Urrutia, Jacques Fellay, Lluis Quintana-Murci, Hélène Quach, Friederike Jönsson, Cherie Green, Olivier Lantz, Lars Rogge, Stéphanie Thomas, Vincent Rouilly, Barbara Piasecka, Yoong Wearn Lim, Claire Leloup, Cécile Alanio, Isabelle Peguillet, Christian Hammer, Benoit Beitz, Magnus Fontes, Magge Zepeda, Matthew L. Albert, Valentina Libri, James P. Di Santo, Etienne Patin, Milena Hasan, François Huetz, Darragh Duffy, Vougny, Marie-Christine, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Lund University [Lund], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ecole Polytechnique Fédérale de Lausanne (EPFL), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Anticorps en Thérapie et Pathologie, Genentech, Inc. [San Francisco], Immunorégulation, Biologie des Populations Lymphocytaires, Institut Curie [Paris], International Group for Data Analysis (IGDA), Immunité Innée - Innate Immunity, This work benefited from support of the French government’s program ‘Investissement d’Avenir’, managed by the Agence Nationale de la Recherche (reference 10-LABX-69-01). J.B. is a member of the LCCC Linnaeus Center and the ELLIIT Excellence Center at Lund University and is supported by the ELLIIT Excellence Center., The Milieu Intérieur Consortium : Laurent Abel, Andres Alcover, Kalle Astrom, Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James P. Di Santo, Françoise Dromer, Darragh Duffy, Gérard Eberl, Jost Enninga, Jacques Fellay, Antonio Freitas, Odile Gelpi, Ivo Gomperts Boneca, Serge Hercberg, Olivier Lantz, Claude Leclerc, Hugo Mouquet, Etienne Patin, Sandra Pellegrini, Stanislas Pol, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Vassili Soumelis, Frédéric Tangy, Eric Tartour, Antoine Toubert, Marie-Noëlle Ungeheuer, Lluís Quintana-Murci & Matthew L. Albert, ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lausanne (UNIL), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]

Subjects
Adult, Male, 0301 basic medicine, MESH: Immunity, Innate/genetics, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Immunophenotyping, MESH: Genetic Variation/immunology, Immunology, Genome-wide association study, Disease, Adaptive Immunity, Biology, Immunophenotyping, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Immune system, Immunity, Genetic variation, Humans, Immunology and Allergy, Aged, Genetic association, MESH: Aged, Innate immune system, MESH: Humans, MESH: Middle Aged, Genetic Variation, MESH: Adult, Environmental exposure, Middle Aged, Immunity, Innate, MESH: Male, 3. Good health, 030104 developmental biology, MESH: Young Adult, MESH: Genome-Wide Association Study, MESH: Adaptive Immunity/genetics, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Female, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

A Publisher Correction to this article was published on 03 May 2018; International audience; The quantification and characterization of circulating immune cells provide key indicators of human health and disease. To identify the relative effects of environmental and genetic factors on variation in the parameters of innate and adaptive immune cells in homeostatic conditions, we combined standardized flow cytometry of blood leukocytes and genome-wide DNA genotyping of 1,000 healthy, unrelated people of Western European ancestry. We found that smoking, together with age, sex and latent infection with cytomegalovirus, were the main non-genetic factors that affected variation in parameters of human immune cells. Genome-wide association studies of 166 immunophenotypes identified 15 loci that showed enrichment for disease-associated variants. Finally, we demonstrated that the parameters of innate cells were more strongly controlled by genetic variation than were those of adaptive cells, which were driven by mainly environmental exposure. Our data establish a resource that will generate new hypotheses in immunology and highlight the role of innate immunity in susceptibility to common autoimmune diseases.

Published
2018
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52. Semi-automated and standardized cytometric procedures for multi-panel and multi-parametric whole blood immunophenotyping

Author

Hasan, Milena, Beitz, Benoit, Rouilly, Vincent, Libri, Valentina, Urrutia, Alejandra, Duffy, Darragh, Cassard, Lydie, Di Santo, James P., Mottez, Estelle, Quintana-Murci, Lluis, Albert, Matthew L., Rogge, Lars, The Milieu Interieur, Consortium, Centre d'Immunologie Humaine (CIH), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Immunobiologie des Cellules Dendritiques, Immunité Innée - Innate Immunity, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Immunorégulation, This work benefited from support of the French government's Invest in the Future Program, managed by the Agence Nationale de la Recherche (ANR, reference 10-LABX-69-01), The Milieu Intérieur Consortium is composed of the following team leaders: Laurent Abel (Hôpital Necker), Andres Alcover, Philippe Bousso, Pierre Bruhns, Ana Cumano, Marc Daëron, Cécile Delval, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Antonio Freitas, Odile Gelpi, Ivo Gomperts-Boneca, Serge Hercberg (Université Paris 13), Olivier Lantz (Institut Curie), Claude Leclerc, Hugo Mouquet, Sandra Pellegrini, Stanislas Pol (Hôpital Côchin), Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Vassili Soumelis (Institut Curie), Frédéric Tangy, Eric Tartour (Hôpital Européen George Pompidou), Antoine Toubert (Hôpital Saint-Louis), Marie-Noëlle Ungeheuer, Lluis Quintana-Murci, and Matthew L. Albert., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Vougny, Marie-Christine, and Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID

Subjects
MESH: Killer Cells, Natural, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Flow Cytometry/methods, Neutrophils, T-Lymphocytes, Immunology, Population, Context (language use), MESH: Neutrophils, MESH: Monocytes, Monocytes, Specimen Handling, Immunophenotyping, Automation, Antigens, CD, MESH: B-Lymphocytes, Humans, Immunology and Allergy, Medicine, education, MESH: Automation, Laboratory/methods, Whole blood, Automation, Laboratory, B-Lymphocytes, education.field_of_study, MESH: Humans, Multi parametric, MESH: Dendritic Cells, business.industry, MESH: Immunophenotyping/methods, MESH: Antigens, CD/immunology, Dendritic Cells, Flow Cytometry, MESH: Specimen Handling/methods, Standardization, 3. Good health, Killer Cells, Natural, MESH: T-Lymphocytes, Robotic systems, Reference values, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, Cytometry
Abstract

International audience; Immunophenotyping by multi-parametric flow cytometry is the cornerstone technology for enumeration and characterization of immune cell populations in health and disease. Standardized procedures are essential to allow for inter-individual comparisons in the context of population based or clinical studies. Herein we report the approach taken by the Milieu Intérieur Consortium, highlighting the standardized and automated procedures used for immunophenotyping of human whole blood samples. We optimized eight-color antibody panels and procedures for staining and lysis of whole blood samples, and implemented pre-analytic steps with a semi-automated workflow using a robotic system. We report on four panels that were designed to enumerate and phenotype major immune cell populations (PMN, T, B, NK cells, monocytes and DC). This work establishes a foundation for defining reference values in healthy donors. Our approach provides robust protocols for affordable, semi-automated eight-color cytometric immunophenotyping that can be used in population-based studies and clinical trial settings.

Published
2015
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53. Automated flow cytometric analysis across large numbers of samples and cell types

Author

Lluis Quintana-Murci, Valentina Libri, Bernard Chalmond, Xiaoyi Chen, Vincent Rouilly, Benoit Beitz, Alejandra Urrutia, Matthew L. Albert, Lars Rogge, Milena Hasan, Etienne Patin, Darragh Duffy, Benno Schwikowski, Biologie systémique - Systems Biology, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Analyse, Géométrie et Modélisation (AGM - UMR 8088), CY Cergy Paris Université (CY)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie Humaine (CIH), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunobiologie des Cellules Dendritiques, Immunorégulation, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre de Mathématiques et de Leurs Applications (CMLA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Université de Cergy Pontoise (UCP), Université Paris-Seine, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Non Linéaire de Nice Sophia-Antipolis (INLN), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), The Milieu Intérieur Consortium is composed of the following team leaders: Laurent Abel (Hôpital Necker), Andres Alcover, Philippe Bousso, Pierre Bruhns, Ana Cumano, Marc Daëron, Cécile Delval, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Odile Gelpi, Antonio Freitas, Ivo Gomperts-Boneca, Serge Hercberg (Université Paris 13), Olivier Lantz (Institut Curie), Claude Leclerc, Hugo Mouquet, Sandra Pellegrini, Stanislas Pol (Hôpital Côchin), Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Vassili Soumelis (Institut Curie), Frédéric Tangy, Eric Tartour (Hôpital Européen George Pompidou), Antoine Toubert (Hôpital Saint-Louis), Marie-Noëlle Ungeheuer, Lluis Quintana-Murci2, Matthew L. Albert3.Additional information can be found at: http://www.pasteur.fr/labex/milieu-interieur., Kop, Marie-Luce, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)

Subjects
Multidimensional analysis, [SDV.IMM] Life Sciences [q-bio]/Immunology, Neutrophils, Computer science, T-Lymphocytes, Pipeline (computing), Statistics as Topic, Immunology, Flow cytometry, Gating, Bioinformatics, Monocytes, Automation, T-Lymphocyte Subsets, Bayesian information criterion, Cluster Analysis, Humans, Immunology and Allergy, Population-based cohort, Cluster analysis, Automation, Laboratory, B-Lymphocytes, business.industry, Bayes Theorem, Dendritic Cells, Reference Standards, Mixture model, Standardization, Killer Cells, Natural, Identification (information), ComputingMethodologies_PATTERNRECOGNITION, [SDV.IMM]Life Sciences [q-bio]/Immunology, Algorithms, Biological system, business, Software
Abstract

International audience; Multi-parametric flow cytometry is a key technology for characterization of immune cell phenotypes. However, robust high-dimensional post-analytic strategies for automated data analysis in large numbers of donors are still lacking. Here, we report a computational pipeline, called FlowGM, which minimizes operator input, is insensitive to compensation settings, and can be adapted to different analytic panels. A Gaussian Mixture Model (GMM)-based approach was utilized for initial clustering, with the number of clusters determined using Bayesian Information Criterion. Meta-clustering in a reference donor permitted automated identification of 24 cell types across four panels. Cluster labels were integrated into FCS files, thus permitting comparisons to manual gating. Cell numbers and coefficient of variation (CV) were similar between FlowGM and conventional gating for lymphocyte populations, but notably FlowGM provided improved discrimination of "hard-to-gate" monocyte and dendritic cell (DC) subsets. FlowGM thus provides rapid high-dimensional analysis of cell phenotypes and is amenable to cohort studies.

Published
2015
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54. Bulgecin A: The Key to a Broad-Spectrum Inhibitor That Targets Lytic Transglycosylases

Author

Williams, Allison H., Wheeler, Richard, Thiriau, Constance, Haouz, Ahmed, Taha, Muhamed-Kheir, Boneca, Ivo, Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall (BGPB), Institut Pasteur [Paris], Groupe Avenir, Institut National de la Santé et de la Recherche Médicale (INSERM), Cristallographie (Plateforme) - Crystallography (Platform), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Infections Bactériennes Invasives, This work was supported by an ERC starting grant (PGNfromSHAPEtoVIR 202283) to Ivo Gomperts Boneca and an ANR (Agence National de la Recherche) grant number ANR-14-CE14-0003 to MKT. This study has received funding from the French Government′s Investissement d′Avenir program, Laboratoire d′Excellence 'Integrative Biology of Emerging Infectious Diseases' (grant n°ANR-10-LABX-62-IBEID)., ANR-14-CE14-0003,ORBiMP,Déjouer la résistance aux beta-lactamines des méningocoques et pneumocoques(2014), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, Neisseria, bulgecin, lytic transglycosylase, beta‐lactam, peptidoglycan, beta-lactam, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Article
Abstract

International audience; Lytic transglycosylases (Lts) are involved in recycling, cell division, and metabolism of the peptidoglycan. They have been understudied for their usefulness as potential antibacterial targets due to their high redundancy in Gram-negative bacteria. Bulgecin A is an O-sulphonated glycopeptide that targets primarily soluble lytic tranglycosylases (Slt). It has been shown that bulgecin A increases the efficacy of β-lactams that target penicillin bindings proteins (PBPs). Here, we present the high-resolution crystal structure of LtgA from Neisseria meningitidis strain MC58, a membrane bound homolog of Escherichia coli Slt, in complex with bulgecin A. The LtgA-bulgecin A complex reveals the mechanism of inhibition by bulgecin A at near atomic resolution. We further demonstrate that bulgecin A is not only a potent inhibitor of LtgA, but most importantly, it restores the efficacy of β-lactam antibiotics in strains of N. meningitidis and Neisseria gonorrhoeae that have reduced susceptibility to β-lactams. This is particularly relevant for N. gonorrhoeae where no vaccines are available. This work illustrates how best to target dangerous pathogens using a multiple drug target approach, a new and alternative approach to fighting antibiotic resistance.

Published
2017
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55. Peptidoglycan Crosslinking Relaxation Plays an Important Role in Staphylococcus aureus WalKR-Dependent Cell Viability

Author

Yves-Marie Coïc, Aurélia Delauné, Sarah Dubrac, Olivier Poupel, Adeline Mallet, Tarek Msadek, Biologie des Bactéries Pathogènes à Gram-positif, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Microscopie ultrastructurale (plate-forme), Institut Pasteur [Paris], Chimie des biomolécules, This work was supported by research funds from the European Commission (StaphDynamics [LHSM-CT-2006-019064] and BaSysBio [LSHG-CT-2006-037469] grants), the Centre National de la Recherche Scientifique (CNRS URA 2172), Agence Nationale de la Recherche (ANR GrabIron and NaBab) and the Institut Pasteur (PTR N°256 and PTR N°336). Aurelia Delaune received a Young Scientist Fellowship from the Conseil Pasteur-Weizmann., We would like to thank Fritz Götz for the kind gift of plasmid pCXlss7 and many helpful suggestions, as well as Marie-Christine Prévost (Institut Pasteur, Ultrastructural Microscopy Platform), Françoise Baleux (Institut Pasteur, Chemistry of Biomolecules), Ivo Gomperts-Boneca and Simon J. Foster for helpful discussion., ANR-08-ALIA-0011,NABAB,Stratégie Non AntiBiotique Anti-Bactéries pathogènes : exploration des capacités inhibitrices des écosystèmes naturels contre les contaminations à S. aureus en contexte laitier(2008), European Project: 35105,STAPHDYNAMICS, European Project: 38901,BASYSBIO, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)

Subjects
Cell division, Hydrolases, MESH: Carbohydrate Metabolism, lcsh:Medicine, chemistry.chemical_compound, Endopeptidase activity, Cell Wall, MESH: Staphylococcus aureus, lcsh:Science, MESH: Endopeptidases, MESH: Bacterial Proteins, Staphylococci, MESH: Microbial Viability, 0303 health sciences, MESH: Gene Expression Regulation, Bacterial, Multidisciplinary, MESH: Peptidoglycan, MESH: Protein Multimerization, Hydrolysis, MESH: Gene Expression Regulation, Enzymologic, Microbial Growth and Development, Bacterial Pathogens, MESH: Hydrolases, Host-Pathogen Interaction, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Carbohydrate Sequence, Biochemistry, Carbohydrate Metabolism, MESH: Hydrolysis, Research Article, Cell wall thickening, Staphylococcus aureus, MESH: Organisms, Genetically Modified, Peptidoglycan, Biology, Models, Biological, Microbiology, Gene Expression Regulation, Enzymologic, Molecular Genetics, Cell wall, 03 medical and health sciences, MESH: Cell Wall, Bacterial Proteins, Endopeptidases, Genetics, Gene Regulation, Viability assay, Microbial Pathogens, Microbial Metabolism, 030304 developmental biology, Gram Positive, MESH: Carbohydrate Sequence, Microbial Viability, Organisms, Genetically Modified, 030306 microbiology, lcsh:R, Autolysin, MESH: Models, Biological, Gene Expression Regulation, Bacterial, MESH: Multiprotein Complexes, Regulon, chemistry, Multiprotein Complexes, lcsh:Q, Protein Multimerization
Abstract

International audience; The WalKR two-component system is essential for viability of Staphylococcus aureus, a major pathogen. We have shown that WalKR acts as the master controller of peptidoglycan metabolism, yet none of the identified regulon genes explain its requirement for cell viability. Transmission electron micrographs revealed cell wall thickening and aberrant division septa in the absence of WalKR, suggesting its requirement may be linked to its role in coordinating cell wall metabolism and cell division. We therefore tested whether uncoupling autolysin gene expression from WalKR-dependent regulation could compensate for its essential nature. Uncoupled expression of genes encoding lytic transglycosylases or amidases did not restore growth to a WalKR-depleted strain. We identified only two WalKR-regulon genes whose expression restored cell viability in the absence of WalKR: lytM and ssaA. Neither of these two genes are essential under our conditions and a ΔlytM ΔssaA mutant does not present any growth defect. LytM is a glycyl-glycyl endopeptidase, hydrolyzing the pentaglycine interpeptide crossbridge, and SsaA belongs to the CHAP amidase family, members of which such as LysK and LytA have been shown to have D-alanyl-glycyl endopeptidase activity, cleaving between the crossbridge and the stem peptide. Taken together, our results strongly suggest that peptidoglycan crosslinking relaxation through crossbridge hydrolysis plays a crucial role in the essential requirement of the WalKR system for cell viability.

Published
2011
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56. A matter of life and death: cell wall homeostasis and the WalKR (YycGF) essential signal transduction pathway

Author

Paola Bisicchia, Sarah Dubrac, Kevin M. Devine, Tarek Msadek, Biologie des Bactéries Pathogènes à Gram-positif, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Trinity College Dublin, Work in the Biology of Gram‐positive Pathogens Unit (Institut Pasteur) was supported by research funds to T.M. from the European Commission (Grants BACELL Health, LSHG‐CT‐2004‐503468, StaphDynamics, LHSM‐CT‐2006–019064, and BaSysBio, LSHG‐CT‐2006‐037469), as well as research funds from the Centre National de la Recherche Scientifique (CNRS URA 2172) and the Institut Pasteur (Grand Programme Horizontal N°9). Work at the Smurfit Institute of Genetics was supported by grants to KMD from Science Foundation Ireland (Principal Investigator Award, 03/IN3/B409), from the EU (BACELL Health, LSHG‐CT‐2004‐503468) and from Enterprise Ireland (SC/02/109)., The authors would like to thank the anonymous reviewers for their constructive comments and useful suggestions. S.D. and T.M. would like to thank Ivo Gomperts‐Boneca and James A. Hoch for helpful discussion., European Project: 26873,BACELL HEALTH, European Project: 35105,STAPHDYNAMICS, European Project: 38901,BASYSBIO, and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
Histidine Kinase, Cell division, Operon, [SDV]Life Sciences [q-bio], Peptidoglycan, Bacillus subtilis, Gram-Positive Bacteria, Regulon, Microbiology, 03 medical and health sciences, chemistry.chemical_compound, Cell Wall, Homeostasis, Molecular Biology, 030304 developmental biology, 0303 health sciences, biology, 030306 microbiology, Histidine kinase, Gene Expression Regulation, Bacterial, biology.organism_classification, Cell biology, Biochemistry, chemistry, Genes, Bacterial, Signal transduction, Protein Kinases, Function (biology), Signal Transduction
Abstract

International audience; The WalK/WalR (aka YycG/YycF) two-component system (TCS), originally identified in Bacillus subtilis, is very highly conserved and specific to low G+C Gram-positive bacteria, including a number of important pathogens. An unusual feature is that this system is essential for viability in most of these bacteria. Recent studies have revealed conserved functions for this system, defining this signal transduction pathway as a crucial regulatory system for cell wall metabolism, that we have accordingly renamed WalK/WalR. Here we review the cellular role of the WalK/WalR TCS in different bacterial species, focusing on the function of genes in its regulon, as well as variations in walRK operon structure and the composition of its regulon. We also discuss the nature of its essentiality and the potential type of signal being sensed. The WalK histidine kinase of B. subtilis has been shown to localize to the divisome and we suggest that the WalKR system acts as an information conduit between extracytoplasmic cellular structures and intracellular processes required for their synthesis, playing a vital role in effectively co-ordinating peptidoglycan plasticity with the cell division process.

Published
2008
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