title: Recombinant BCG Expressing ESX-1 of Mycobacterium marinum Combines Low Virulence with Cytosolic Immune Signaling and Improved TB Protection.
abstract: 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-1Mmar) 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-1Mmarconfers superior protection relative to parental BCG against challenges with highly virulent M. tuberculosis.
authors.affiliation: 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.
authors.forename: Matthias I
authors.initials: MI
authors.lastname: Gröschel
authors.affiliation: Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France.
authors.forename: Fadel
authors.initials: F
authors.lastname: Sayes
authors.affiliation: 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.
authors.forename: Sung Jae
authors.initials: SJ
authors.lastname: Shin
authors.affiliation: Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France.
authors.forename: Wafa
authors.initials: W
authors.lastname: Frigui
authors.affiliation: Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Pawlik
authors.affiliation: Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France.
authors.forename: Mickael
authors.initials: M
authors.lastname: Orgeur
authors.affiliation: Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France.
authors.forename: Robin
authors.initials: R
authors.lastname: Canetti
authors.affiliation: Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Honoré
authors.affiliation: Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France.
authors.forename: Roxane
authors.initials: R
authors.lastname: Simeone
authors.affiliation: Department of Pulmonary Diseases & Tuberculosis, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands.
authors.forename: Tjip S
authors.initials: TS
authors.lastname: van der Werf
authors.affiliation: 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.
authors.forename: Wilbert
authors.initials: W
authors.lastname: Bitter
authors.affiliation: 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.
authors.forename: Sang-Nae
authors.initials: SN
authors.lastname: Cho
authors.affiliation: Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France.
authors.forename: Laleh
authors.initials: L
authors.lastname: Majlessi
authors.affiliation: Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France. Electronic address: roland.brosch@pasteur.fr.
authors.forename: Roland
authors.initials: R
authors.lastname: Brosch
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000276:immunology*; D001426:Bacterial Proteins / Q000378:metabolism*; D003600:Cytosol / Q000276:immunology*; D005816:Genetic Complementation Test; D054884:Host-Pathogen Interactions / Q000276:immunology; D007113:Immunity, Innate; D007114:Immunization; D016513:Mice, SCID; D019910:Mycobacterium marinum / Q000472:pathogenicity*; D010588:Phagosomes / Q000378:metabolism; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control*; D014614:Vaccines, Synthetic / Q000276:immunology*; D014774:Virulence
chemical_list: D001500:BCG Vaccine; D001426:Bacterial Proteins; D014614:Vaccines, Synthetic
keywords: ESX/type VII secretion; Mycobacterium marinum; Mycobacterium tuberculosis; cytosolic pattern recognition; innate immune signaling; recombinant BCG; tuberculosis; vaccination