Recombinant BCG Expressing ESX-1 of Mycobacterium marinum Combines Low Virulence with Cytosolic Immune Signaling and Improved TB Protection.

Autor:	Gröschel MI; Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France; Department of Pulmonary Diseases & Tuberculosis, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands., Sayes F; Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France., Shin SJ; Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 03722 Seoul, South Korea., Frigui W; Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France., Pawlik A; Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France., Orgeur M; Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France., Canetti R; Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France., Honoré N; Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France., Simeone R; Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France., van der Werf TS; Department of Pulmonary Diseases & Tuberculosis, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands., Bitter W; Department of Medical Microbiology and Infection Control, VU University Medical Center, 1081 HZ Amsterdam, the Netherlands; Section Molecular Microbiology, Amsterdam Institute of Molecules, Medicine and Systems, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, the Netherlands., Cho SN; Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 03722 Seoul, South Korea., Majlessi L; Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France., Brosch R; Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France. Electronic address: roland.brosch@pasteur.fr.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2017 Mar 14; Vol. 18 (11), pp. 2752-2765.
DOI:	10.1016/j.celrep.2017.02.057
Abstrakt:	Recent insights into the mechanisms by which Mycobacterium tuberculosis, the etiologic agent of human tuberculosis, is recognized by cytosolic nucleotide sensors have opened new avenues for rational vaccine design. The only licensed anti-tuberculosis vaccine, Mycobacterium bovis BCG, provides limited protection. A feature of BCG is the partial deletion of the ESX-1 type VII secretion system, which governs phagosomal rupture and cytosolic pattern recognition, key intracellular phenotypes linked to increased immune signaling. Here, by heterologously expressing the esx-1 region of Mycobacterium marinum in BCG, we engineered a low-virulence, ESX-1-proficient, recombinant BCG (BCG::ESX-1 Mmar ) that induces the cGas/STING/TBK1/IRF-3/type I interferon axis and enhances AIM2 and NLRP3 inflammasome activity, resulting in both higher proportions of CD8 + T cell effectors against mycobacterial antigens shared with BCG and polyfunctional CD4 + Th1 cells specific to ESX-1 antigens. Importantly, independent mouse vaccination models show that BCG::ESX-1 Mmar confers superior protection relative to parental BCG against challenges with highly virulent M. tuberculosis. (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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