Recombinant BCG Expressing ESX-1 of Mycobacterium marinum Combines Low Virulence with Cytosolic Immune Signaling and Improved TB Protection
Matthias I. Gröschel,
Fadel Sayes,
Sung Jae Shin,
Wafa Frigui,
Alexandre Pawlik,
Mickael Orgeur,
Robin Canetti,
Nadine Honoré,
Roxane Simeone,
Tjip S. van der Werf,
Wilbert Bitter,
Sang-Nae Cho,
Laleh Majlessi,
Roland Brosch
Affiliations
Matthias I. Gröschel
Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France
Fadel Sayes
Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France
Sung Jae Shin
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
Wafa Frigui
Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France
Alexandre Pawlik
Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France
Mickael Orgeur
Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France
Robin Canetti
Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France
Nadine Honoré
Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France
Roxane Simeone
Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France
Tjip S. van der Werf
Department of Pulmonary Diseases & Tuberculosis, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands
Wilbert Bitter
Department of Medical Microbiology and Infection Control, VU University Medical Center, 1081 HZ Amsterdam, the Netherlands
Sang-Nae Cho
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
Laleh Majlessi
Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France
Roland Brosch
Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France
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-1Mmar confers superior protection relative to parental BCG against challenges with highly virulent M. tuberculosis.
