Relative contribution of IL-1α, IL-1β and TNF to the host response to Mycobacterium tuberculosis and attenuated M. bovis BCG

Authors

  • Marie-Laure Bourigault,

    1. CNRS, UMR7355, Orleans, France
    2. University of Orleans, Experimental and Molecular Immunology and Neurogenetics, Orleans, France
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  • Noria Segueni,

    1. CNRS, UMR7355, Orleans, France
    2. University of Orleans, Experimental and Molecular Immunology and Neurogenetics, Orleans, France
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  • Stéphanie Rose,

    1. CNRS, UMR7355, Orleans, France
    2. University of Orleans, Experimental and Molecular Immunology and Neurogenetics, Orleans, France
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  • Nathalie Court,

    1. CNRS, UMR7355, Orleans, France
    2. University of Orleans, Experimental and Molecular Immunology and Neurogenetics, Orleans, France
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  • Rachel Vacher,

    1. CNRS, UMR7355, Orleans, France
    2. University of Orleans, Experimental and Molecular Immunology and Neurogenetics, Orleans, France
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  • Virginie Vasseur,

    1. CNRS, UMR7355, Orleans, France
    2. University of Orleans, Experimental and Molecular Immunology and Neurogenetics, Orleans, France
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  • François Erard,

    1. CNRS, UMR7355, Orleans, France
    2. University of Orleans, Experimental and Molecular Immunology and Neurogenetics, Orleans, France
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  • Marc Le Bert,

    1. CNRS, UMR7355, Orleans, France
    2. University of Orleans, Experimental and Molecular Immunology and Neurogenetics, Orleans, France
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  • Irene Garcia,

    1. Department of Pathology and Immunology, University of Geneva Medical School, Geneva, Switzerland
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  • Yoichiro Iwakura,

    1. Center for Experimental Medicine, The Institute of Medical Science, University of Tokyo, Tokyo, Japan
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  • Muazzam Jacobs,

    1. Division of Immunology, Institute of Infectious Disease and Molecular Medicine, Health Sciences Faculty, University of Cape Town, Cape Town, South Africa
    2. National Health Laboratory Service, Cape Town, South Africa
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  • Bernhard Ryffel,

    1. CNRS, UMR7355, Orleans, France
    2. University of Orleans, Experimental and Molecular Immunology and Neurogenetics, Orleans, France
    3. Division of Immunology, Institute of Infectious Disease and Molecular Medicine, Health Sciences Faculty, University of Cape Town, Cape Town, South Africa
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  • Valerie F. J. Quesniaux

    Corresponding author
    1. CNRS, UMR7355, Orleans, France
    2. University of Orleans, Experimental and Molecular Immunology and Neurogenetics, Orleans, France
    • Correspondence

      Valerie F. J. Quesniaux, INEM UMR7355, 3B rue de la Ferollerie, 45071 Orleans, France.

      Tel: +33-2-38-25-54-39;

      Fax: +33-2-38-25-79-79;

      E-mail: quesniaux@cnrs-orleans.fr

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  • Funding information
  • CNRS through International Associated Laboratory “TB Immunity” (LIA n°236) and Le Studium.

Abstract

TNF and IL-1 are major mediators involved in severe inflammatory diseases against which therapeutic neutralizing antibodies are developed. However, both TNF and IL-1 receptor pathways are essential for the control of Mycobacterium tuberculosis infection, and it is critical to assess the respective role of IL-1α, IL-1β, and TNF. Using gene-targeted mice we show that absence of both IL-1α and IL-1β recapitulates the uncontrolled M. tuberculosis infection with increased bacterial burden, exacerbated lung inflammation, high IFNγ, reduced IL-23 p19 and rapid death seen in IL-1R1-deficient mice. However, presence of either IL-1α or IL-1β in single-deficient mice is sufficient to control acute M. tuberculosis infection, with restrained bacterial burden and lung pathology, in conditions where TNF deficient mice succumbed within 4 weeks with overwhelming infection. Systemic infection by attenuated M. bovis BCG was controlled in the absence of functional IL-1 pathway, but not in the absence of TNF. Therefore, although both IL-1α and IL-1β are required for a full host response to virulent M. tuberculosis, the presence of either IL-1α or IL-1β allows some control of acute M. tuberculosis infection, and IL-1 pathway is dispensable for controlling M. bovis BCG acute infection. This is in sharp contrast with TNF, which is essential for host response to both attenuated and virulent mycobacteria and may have implications for anti-inflammatory therapy with IL-1β neutralizing antibodies.

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