المؤلفون: Hayley J. Newton, Malcolm J. McConville, Iain D. Hay, Asma Ul Husna, Jonathan J. Wilksch, Nancy Wang, Dianna M Hocking, Richard A. Strugnell, Simon A. Cobbold, Trevor Lithgow, Mark R. Davies

المصدر: Biochemical Journal. 476:3435-3453

مصطلحات موضوعية: Male, Salmonella typhimurium, Mutant, Virulence, medicine.disease_cause, Biochemistry, Legionella pneumophila, Microbiology, Mice, 03 medical and health sciences, chemistry.chemical_compound, Bacterial Proteins, Methylthioadenosine nucleosidase, medicine, Animals, Humans, N-Glycosyl Hydrolases, Molecular Biology, Escherichia coli, 030304 developmental biology, 0303 health sciences, biology, 030306 microbiology, Gene Expression Regulation, Bacterial, Cell Biology, biology.organism_classification, Multifunctional Enzymes, S-Adenosylhomocysteine, Mice, Inbred C57BL, Complementation, Spermidine, Purine-Nucleoside Phosphorylase, chemistry, Salmonella enterica, Salmonella Infections, Female

الوصف: Key physiological differences between bacterial and mammalian metabolism provide opportunities for the development of novel antimicrobials. We examined the role of the multifunctional enzyme S-adenosylhomocysteine/Methylthioadenosine (SAH/MTA) nucleosidase (Pfs) in the virulence of S. enterica var Typhimurium (S. Typhimurium) in mice, using a defined Pfs deletion mutant (i.e. Δpfs). Pfs was essential for growth of S. Typhimurium in M9 minimal medium, in tissue cultured cells, and in mice. Studies to resolve which of the three known functions of Pfs were key to murine virulence suggested that downstream production of autoinducer-2, spermidine and methylthioribose were non-essential for Salmonella virulence in a highly sensitive murine model. Mass spectrometry revealed the accumulation of SAH in S. Typhimurium Δpfs and complementation of the Pfs mutant with the specific SAH hydrolase from Legionella pneumophila reduced SAH levels, fully restored growth ex vivo and the virulence of S. Typhimurium Δpfs for mice. The data suggest that Pfs may be a legitimate target for antimicrobial development, and that the key role of Pfs in bacterial virulence may be in reducing the toxic accumulation of SAH which, in turn, suppresses an undefined methyltransferase.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a6b7bc46dcddcecfccd050e96047228bTest
https://doi.org/10.1042/bcj20190297Test

المؤلفون: Nancy Wang, Richard A. Strugnell, Leigh A. Knodler

المصدر: Cell Host Microbe

مصطلحات موضوعية: Virulence, Biology, Salmonella typhi, Microbiology, complex mixtures, Typhoid fever, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Virology, medicine, Animals, Humans, Typhoid Fever, Gene, 030304 developmental biology, Toxins, Biological, Genetics, 0303 health sciences, medicine.disease, bacterial infections and mycoses, bacteria, Parasitology, 030217 neurology & neurosurgery

الوصف: Salmonella enterica serovar Typhi causes typhoid fever only in humans. Murine infection with S. Typhimurium is used as a typhoid model, but its relevance to human typhoid is limited. Non-obese diabetic-scid IL2rγnull mice engrafted with human hematopoietic stem cells (hu-SRC-SCID) are susceptible to lethal S. Typhi infection. In this study, we use a high-density S. Typhi transposon library in hu-SRC-SCID mice to identify virulence loci using transposon-directed insertion site sequencing (TraDIS). Vi capsule, LPS and aromatic amino acid biosynthesis were essential for virulence, along with the siderophore salmochelin. However, in contrast to the murine S. Typhimurium model, neither the PhoPQ two-component system nor the SPI-2 pathogenicity island were required for lethal S. Typhi infection, nor was the CdtB typhoid toxin. These observations highlight major differences in the pathogenesis of typhoid and nontyphoidal Salmonella infections and demonstrate the utility of humanized mice for understanding the pathogenesis of a human-specific pathogen.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a86725be1b246bda62576593a64f3aa8Test
https://pubmed.ncbi.nlm.nih.gov/31447308Test

المؤلفون: Anna C. Seale, Steven Y. C. Tong, Jonathan R. Carapetis, Ankur Mutreja, David Price, James A. Berkley, Pierre R. Smeesters, Stephen D. Bentley, Sebastián Duchêne, John A. Lees, Hannah R Frost, Kate A. Worthing, Matthew T. G. Holden, Philip M. Giffard, Bart J. Currie, John D. Fraser, Olga Berking, Allan Saul, Mark J. Walker, Richard A. Strugnell, Nicole J. Moreland, Simon R. Harris, Julian Parkhill, Rebecca J. Towers, Deborah A Williamson, Amanda J. Cork, Gordon Dougan, Tania Rivera-Hernandez, Jake A. Lacey, Liam McIntyre, G. S. Chhatwal, Trevor Lithgow, Andrew C Steer, René Bergmann, Patric Nitsche-Schmitz, Mark R. Davies, Rosângela Stadnick Lauth de Almeida Torres, Sophia David

المساهمون: Davies, Mark R [0000-0001-6141-5179], Frost, Hannah R [0000-0002-1543-2805], Price, David J [0000-0003-0076-3123], Holden, Matthew TG [0000-0002-4958-2166], Berkley, James A [0000-0002-1236-849X], Strugnell, Richard A [0000-0003-0614-5641], Parkhill, Julian [0000-0002-7069-5958], Walker, Mark J [0000-0001-7423-2769], Apollo - University of Cambridge Repository, HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany., University of St Andrews. School of Medicine, University of St Andrews. Infection and Global Health Division, University of St Andrews. Biomedical Sciences Research Complex, University of St Andrews. Infection Group

المصدر: Nature genetics, 51 (6
Nature genetics
United Kingdom
United States

مصطلحات موضوعية: Streptococcal Infections -- prevention & control, Antigens, Bacterial -- genetics -- immunology, Streptococcus pyogenes, Population, Genomics, Genome-wide association study, Computational biology, Biology, medicine.disease_cause, Genome, DNA sequencing, Article, 03 medical and health sciences, 0302 clinical medicine, Streptococcal Vaccines -- genetics -- immunology, SDG 3 - Good Health and Well-being, Streptococcal Vaccines, Streptococcal Infections, Genetics, medicine, Genomics -- methods, Humans, QR180 Immunology, education, R2C, Phylogeny, 030304 developmental biology, Comparative genomics, Recombination, Genetic, 0303 health sciences, education.field_of_study, Antigens, Bacterial, ~DC~, DAS, QR Microbiology, Sciences bio-médicales et agricoles, QR, QR180, BDC, 030217 neurology & neurosurgery, Streptococcus pyogenes -- classification -- genetics -- immunology, Genome, Bacterial, Genome-Wide Association Study

الوصف: Group A Streptococcus (GAS; Streptococcus pyogenes) is a bacterial pathogen for which a commercial vaccine for humans is not available. Employing the advantages of high-throughput DNA sequencing technology to vaccine design, we have analyzed 2,083 globally sampled GAS genomes. The global GAS population structure reveals extensive genomic heterogeneity driven by homologous recombination and overlaid with high levels of accessory gene plasticity. We identified the existence of more than 290 clinically associated genomic phylogroups across 22 countries, highlighting challenges in designing vaccines of global utility. To determine vaccine candidate coverage, we investigated all of the previously described GAS candidate antigens for gene carriage and gene sequence heterogeneity. Only 15 of 28 vaccine antigen candidates were found to have both low naturally occurring sequence variation and high (>99%) coverage across this diverse GAS population. This technological platform for vaccine coverage determination is equally applicable to prospective GAS vaccine antigens identified in future studies.
info:eu-repo/semantics/published

وصف الملف: application/pdf; 2 full-text file(s): application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ebe231f38a440c1b55c598477636bc04Test
https://www.repository.cam.ac.uk/handle/1810/316646Test

المؤلفون: David J. Edwards, Stephen Baker, Juliëtte A. Severin, Thomas R. Connor, Jonathan J. Wilksch, Kathryn E. Holt, Catrin E. Moore, Richard A. Strugnell, Paul N. Newton, Hanwei Cao, Mark B. Schultz, Martijn Mensink, David A. B. Dance, Trinh Tuyet Dao, Trung Vu Nguyen, Nguyen Thi Khanh Nhu, Kuntaman Kuntaman, Vien Le Minh, Ruth N. Zadoks, Adam Jenney, Kinh Van Nguyen, Constance Schultsz, Claire L. Gorrie, Sylvain Brisse, Nicholas R. Thomson, Li Yang Hsu, Chris A. Whitehouse, Heiman F. L. Wertheim

المساهمون: Graduate School, AII - Amsterdam institute for Infection and Immunity, Global Health, Medical Microbiology & Infectious Diseases, Pediatric Surgery

المصدر: Proceedings of the National Academy of Sciences of the United States of America, 112(27), E3574-E3581. National Academy of Sciences
Proceedings of the National Academy of Sciences of the U.S.A., 112(27), E3574-E3581. National Academy of Sciences

مصطلحات موضوعية: Klebsiella pneumoniae, Population Dynamics, Virulence, Genomics, Drug resistance, Klebsiella variicola, Genome, Microbiology, 03 medical and health sciences, Antibiotic resistance, Anti-Infective Agents, Bacterial Proteins, Species Specificity, SDG 3 - Good Health and Well-being, Drug Resistance, Multiple, Bacterial, Animals, Humans, Phylogeny, 030304 developmental biology, Cross Infection, 0303 health sciences, Multidisciplinary, biology, 030306 microbiology, Genetic Variation, Outbreak, Sequence Analysis, DNA, biology.organism_classification, Klebsiella Infections, 3. Good health, PNAS Plus, Genes, Bacterial, Public Health, Genome, Bacterial

الوصف: Klebsiella pneumoniae is now recognized as an urgent threat to human health because of the emergence of multidrug-resistant strains associated with hospital outbreaks and hypervirulent strains associated with severe community-acquired infections. K. pneumoniae is ubiquitous in the environment and can colonize and infect both plants and animals. However, little is known about the population structure of K. pneumoniae, so it is difficult to recognize or understand the emergence of clinically important clones within this highly genetically diverse species. Here we present a detailed genomic framework for K. pneumoniae based on whole-genome sequencing of more than 300 human and animal isolates spanning four continents. Our data provide genome-wide support for the splitting of K. pneumoniae into three distinct species, KpI (K. pneumoniae), KpII (K. quasipneumoniae), and KpIII (K. variicola). Further, for K. pneumoniae (KpI), the entity most frequently associated with human infection, we show the existence of >150 deeply branching lineages including numerous multidrug-resistant or hypervirulent clones. We show K. pneumoniae has a large accessory genome approaching 30,000 protein-coding genes, including a number of virulence functions that are significantly associated with invasive community-acquired disease in humans. In our dataset, antimicrobial resistance genes were common among human carriage isolates and hospital-acquired infections, which generally lacked the genes associated with invasive disease. The convergence of virulence and resistance genes potentially could lead to the emergence of untreatable invasive K. pneumoniae infections; our data provide the whole-genome framework against which to track the emergence of such threats.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9a4db5023e28c5d45cc315ec6d6813dfTest
https://pure.amc.nl/en/publications/genomic-analysis-of-diversity-population-structure-virulence-and-antimicrobial-resistance-in-klebsiella-pneumoniae-an-urgent-threat-to-public-healthTest(05c8c211-dec8-48c9-9201-77553357550b).html

المؤلفون: Rohan D. Teasdale, Eva Heinz, Chaille T. Webb, Vladimir A Likic, Rebecca J. Gorrell, Kathryn E. Holt, Terry Kwok, Trevor Lithgow, Richard A. Strugnell, Thomas Naderer, Terence P. Speed, Denisse L. Leyton, Nemin Celik

المصدر: PLoS ONE, Vol 7, Iss 8, p e43245 (2012)
PLoS ONE

مصطلحات موضوعية: Sequence analysis, Science, Amino Acid Motifs, Bacterial genome size, Computational biology, Ralstonia, Biology, Biochemistry, Microbiology, Fusobacteria, Protein Structure, Secondary, Conserved sequence, Transmembrane Transport Proteins, 03 medical and health sciences, Bacterial Proteins, Genome Analysis Tools, Escherichia coli, Humans, Adhesins, Bacterial, Peptide sequence, Phylogeny, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Chlamydiales, 030306 microbiology, Cell Membrane, Computational Biology, Membrane Proteins, Proteins, Biological Transport, Genomics, Protein tertiary structure, Markov Chains, Protein Structure, Tertiary, Bacterial adhesin, Medical Microbiology, Cytochemistry, Medicine, Bacterial outer membrane, Sequence Analysis, Software, Autotransporters, Research Article

الوصف: Autotransporters are secreted proteins that are assembled into the outer membrane of bacterial cells. The passenger domains of autotransporters are crucial for bacterial pathogenesis, with some remaining attached to the bacterial surface while others are released by proteolysis. An enigma remains as to whether autotransporters should be considered a class of secretion system, or simply a class of substrate with peculiar requirements for their secretion. We sought to establish a sensitive search protocol that could identify and characterize diverse autotransporters from bacterial genome sequence data. The new sequence analysis pipeline identified more than 1500 autotransporter sequences from diverse bacteria, including numerous species of Chlamydiales and Fusobacteria as well as all classes of Proteobacteria. Interrogation of the proteins revealed that there are numerous classes of passenger domains beyond the known proteases, adhesins and esterases. In addition the barrel-domain-a characteristic feature of autotransporters-was found to be composed from seven conserved sequence segments that can be arranged in multiple ways in the tertiary structure of the assembled autotransporter. One of these conserved motifs overlays the targeting information required for autotransporters to reach the outer membrane. Another conserved and diagnostic motif maps to the linker region between the passenger domain and barrel-domain, indicating it as an important feature in the assembly of autotransporters.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::169299ba6d9b22054dc7cc3ab85d04e7Test
https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22905239/?tool=EBITest

المؤلفون: Nicolas Tchitchek, Arndt Benecke, Richard A. Strugnell, Christian von Mering, Laurye Van Maele, Wolf-Dietrich Hardt, Jean-Claude Sirard, Kathrin Endt, Andrew J. Macpherson, Mathias Heikenwalder, Baerbel Stecher, Emma Slack, Samuel Chaffron, Andreas J. Mueller

المساهمون: University of Zurich, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Department Klinische Forschung, Gastroenterology Inselspital, Institut des Hautes Études Scientifiques (IHES), IHES, Interactions cellulaires et moléculaires des bactéries pathogènes avec l'hôte, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Institute of Neuropathology, University hospital of Zurich [Zurich], Department of Microbiology and Immunology, University of Melbourne, Swiss National Science Foundation (310000-113623/1, to WDH), the Promedica Foundation (1097/A to WDH), the European Union (SavinMucoPath No. 032296, to WDH and JCS), the Agence Nationale de la Recherche (ISPA, 07-PHYSIO-013-02, to AB) and the Ge´nopole Evry (to AB)., European Project, Université de Lausanne (UNIL), Institut des Hautes Etudes Scientifiques (IHES), Sirard, Jean-Claude, SavinMucoPath No. 032296 - INCOMING

المصدر: PLoS Pathogens
PLoS Pathogens, 2010, 6 (9), pp.e1001097. ⟨10.1371/journal.ppat.1001097⟩
PLoS Pathogens, Public Library of Science, 2010, 6 (9), pp.e1001097. ⟨10.1371/journal.ppat.1001097⟩
PLoS pathogens
PLoS Pathogens, 6 (9)
PLoS Pathogens, Vol 6, Iss 9, p e1001097 (2010)

مصطلحات موضوعية: Immunoglobulin A, Male, Salmonella typhimurium, Infectious Diseases/Gastrointestinal Infections, 2405 Parasitology, Fluorescent Antibody Technique, Gut flora, Immunoenzyme Techniques, Infectious Diseases/Bacterial Infections, Mice, fluids and secretions, Intestinal mucosa, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Biology (General), Intestinal Mucosa, Pathogen, Oligonucleotide Array Sequence Analysis, Mice, Knockout, 0303 health sciences, biology, 2404 Microbiology, O Antigens, Flow Cytometry, 10124 Institute of Molecular Life Sciences, 3. Good health, Microbiology/Immunity to Infections, Diarrhea, Genes, T-Cell Receptor beta, Salmonella Infections, Streptomycin, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, medicine.symptom, Research Article, [SDV.IMM] Life Sciences [q-bio]/Immunology, QH301-705.5, Immunology, Blotting, Western, 10208 Institute of Neuropathology, 610 Medicine & health, Colonisation resistance, Microbiology, digestive system, 03 medical and health sciences, Immune system, 1311 Genetics, Virology, Immunology/Immunity to Infections, Genetics, medicine, 1312 Molecular Biology, Animals, Humans, Microbiome, Molecular Biology, 030304 developmental biology, 2403 Immunology, 030306 microbiology, Gene Expression Profiling, RC581-607, biology.organism_classification, Mice, Inbred C57BL, Immunoglobulin A, Secretory, Immunology/Immune Response, biology.protein, 2406 Virology, Metagenome, 570 Life sciences, Parasitology, Immunologic diseases. Allergy, U7 Systems Biology / Functional Genomics, Biomarkers

الوصف: Many enteropathogenic bacteria target the mammalian gut. The mechanisms protecting the host from infection are poorly understood. We have studied the protective functions of secretory antibodies (sIgA) and the microbiota, using a mouse model for S. typhimurium diarrhea. This pathogen is a common cause of diarrhea in humans world-wide. S. typhimurium (S. tm att, sseD) causes a self-limiting gut infection in streptomycin-treated mice. After 40 days, all animals had overcome the disease, developed a sIgA response, and most had cleared the pathogen from the gut lumen. sIgA limited pathogen access to the mucosal surface and protected from gut inflammation in challenge infections. This protection was O-antigen specific, as demonstrated with pathogens lacking the S. typhimurium O-antigen (wbaP, S. enteritidis) and sIgA-deficient mice (TCRβ−/−δ−/−, JH −/−, IgA−/−, pIgR−/−). Surprisingly, sIgA-deficiency did not affect the kinetics of pathogen clearance from the gut lumen. Instead, this was mediated by the microbiota. This was confirmed using ‘L-mice’ which harbor a low complexity gut flora, lack colonization resistance and develop a normal sIgA response, but fail to clear S. tm att from the gut lumen. In these mice, pathogen clearance was achieved by transferring a normal complex microbiota. Thus, besides colonization resistance ( = pathogen blockage by an intact microbiota), the microbiota mediates a second, novel protective function, i.e. pathogen clearance. Here, the normal microbiota re-grows from a state of depletion and disturbed composition and gradually clears even very high pathogen loads from the gut lumen, a site inaccessible to most “classical” immune effector mechanisms. In conclusion, sIgA and microbiota serve complementary protective functions. The microbiota confers colonization resistance and mediates pathogen clearance in primary infections, while sIgA protects from disease if the host re-encounters the same pathogen. This has implications for curing S. typhimurium diarrhea and for preventing transmission.
Author Summary Numerous pathogens infect the gut. Protection against these infections is mediated by mucosal immune defenses including secreted IgA as well as by the competing intestinal microbiota. However, so far the relative importance of these two different defense mechanisms remains unclear. We addressed this question using the example of non-typhoidal Salmonella (NTS) gut infections which can be spread in stool of infected patients over long periods of time. We used a mouse model to reveal that the intestinal microbiota and the adaptive immune system hold different but complementary functions in fighting NTS infections. A primary Salmonella infection disrupts the normal microbiota and elicits Salmonella-specific sIgA. sIgA prevents disease when the animal is infected with NTS for a second time. However, sIgA was dispensable for pathogen clearance from the gut. Instead, this was mediated by the microbiota. By re-establishing its normal density and composition, the microbiota was necessary and sufficient for terminating long-term fecal Salmonella excretion. This establishes a novel paradigm: The microbiota clears the pathogen from the gut lumen, while sIgA protects from disease upon re-infection with the same pathogen. This has implications for the evolutionary role of sIgA responses as well as for developing microbiota-based therapies for curing infected patients.

وصف الملف: 20844578.pdf - application/pdf; application/pdf; application/application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1d38021bbe5df326d0d653c40d75ca7aTest
https://doi.org/10.5167/uzh-35945Test