A deletion defining a common Asian lineage of<i>Mycobacterium tuberculosis</i>associates with immune subversion

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  • Sandra M. Newton
    *Wellcome Trust Center for Research in Clinical Tropical Medicine, Center for Molecular Microbiology and Infection, and Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, London W2 1PG, United Kingdom;
  • Rebecca J. Smith
    Department of Infection, Immunity, and Inflammation, University of Leicester Medical School, Maurice Shock Building, Leicester LE1 9HN, United Kingdom; and
  • Katalin A. Wilkinson
    *Wellcome Trust Center for Research in Clinical Tropical Medicine, Center for Molecular Microbiology and Infection, and Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, London W2 1PG, United Kingdom;
  • Mark P. Nicol
    Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory 7925, South Africa
  • Natalie J. Garton
    Department of Infection, Immunity, and Inflammation, University of Leicester Medical School, Maurice Shock Building, Leicester LE1 9HN, United Kingdom; and
  • Karl J. Staples
    Department of Infection, Immunity, and Inflammation, University of Leicester Medical School, Maurice Shock Building, Leicester LE1 9HN, United Kingdom; and
  • Graham R. Stewart
    *Wellcome Trust Center for Research in Clinical Tropical Medicine, Center for Molecular Microbiology and Infection, and Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, London W2 1PG, United Kingdom;
  • John R. Wain
    *Wellcome Trust Center for Research in Clinical Tropical Medicine, Center for Molecular Microbiology and Infection, and Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, London W2 1PG, United Kingdom;
  • Adrian R. Martineau
    *Wellcome Trust Center for Research in Clinical Tropical Medicine, Center for Molecular Microbiology and Infection, and Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, London W2 1PG, United Kingdom;
  • Sarah Fandrich
    Department of Infection, Immunity, and Inflammation, University of Leicester Medical School, Maurice Shock Building, Leicester LE1 9HN, United Kingdom; and
  • Timothy Smallie
    *Wellcome Trust Center for Research in Clinical Tropical Medicine, Center for Molecular Microbiology and Infection, and Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, London W2 1PG, United Kingdom;
  • Brian Foxwell
    *Wellcome Trust Center for Research in Clinical Tropical Medicine, Center for Molecular Microbiology and Infection, and Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, London W2 1PG, United Kingdom;
  • Ahmed Al-Obaidi
    Department of Infection, Immunity, and Inflammation, University of Leicester Medical School, Maurice Shock Building, Leicester LE1 9HN, United Kingdom; and
  • Jamila Shafi
    Department of Infection, Immunity, and Inflammation, University of Leicester Medical School, Maurice Shock Building, Leicester LE1 9HN, United Kingdom; and
  • Kumar Rajakumar
    Department of Infection, Immunity, and Inflammation, University of Leicester Medical School, Maurice Shock Building, Leicester LE1 9HN, United Kingdom; and
  • Beate Kampmann
    *Wellcome Trust Center for Research in Clinical Tropical Medicine, Center for Molecular Microbiology and Infection, and Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, London W2 1PG, United Kingdom;
  • Peter W. Andrew
    Department of Infection, Immunity, and Inflammation, University of Leicester Medical School, Maurice Shock Building, Leicester LE1 9HN, United Kingdom; and
  • Loems Ziegler-Heitbrock
    Department of Infection, Immunity, and Inflammation, University of Leicester Medical School, Maurice Shock Building, Leicester LE1 9HN, United Kingdom; and
  • Michael R. Barer
    Department of Infection, Immunity, and Inflammation, University of Leicester Medical School, Maurice Shock Building, Leicester LE1 9HN, United Kingdom; and
  • Robert J. Wilkinson
    *Wellcome Trust Center for Research in Clinical Tropical Medicine, Center for Molecular Microbiology and Infection, and Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, London W2 1PG, United Kingdom;

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<jats:p>Six major lineages of<jats:italic>Mycobacterium tuberculosis</jats:italic>appear preferentially transmitted amongst distinct ethnic groups. We identified a deletion affecting<jats:italic>Rv1519</jats:italic>in CH, a strain isolated from a large outbreak in Leicester U.K., that coincidentally defines the East African-Indian lineage matching a major ethnic group in this city. In broth media, CH grew less rapidly and was less acidic and H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>-tolerant than reference sequenced strains (CDC1551 and H37Rv). Nevertheless, CH was not impaired in its ability to grow in human monocyte-derived macrophages. When compared with CDC1551 and H37Rv, CH induced less protective IL-12p40 and more antiinflammatory IL-10 and IL-6 gene transcription and secretion from monocyte-derived macrophages. It thus appears that CH compensates microbiological attenuation by skewing the innate response toward phagocyte deactivation. Complementation of<jats:italic>Rv1519</jats:italic>, but none of nine additional genes absent from CH compared with the type strain, H37Rv, reversed the capacity of CH to elicit antiinflammatory IL-10 production by macrophages. The<jats:italic>Rv1519</jats:italic>polymorphism in<jats:italic>M. tuberculosis</jats:italic>confers an immune subverting phenotype that contributes to the persistence and outbreak potential of this lineage.</jats:p>

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