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.
Bibliographical noteFunding Information:
We thank Veit Hornung (University of Munich) for kindly providing cGAS and STING K.O. cell lines; Peter Sebo (Czech Academy of Sciences, Prague) for ESAT-6 and CFP-10 proteins, Jean-Marc Ghigo for vector pKOBEG and advice, and Lalita Ramakrishnan, Thierry Soldati, and Timothy Stinear for M.?marinum M strains. We are also grateful to Timothy Stinear for critically reading of the manuscript and advice. M.I.G. receives an MD/PhD scholarship and support from the Graduate School of Medical Sciences, both University of Groningen, the Netherlands. This study was in part supported by the European Union's Horizon 2020 Research and Innovation Program (grant 643381 TBVAC2020), the Agence National de Recherche (grants ANR-14-JAMR-001-02, ANR-14-CE-08-0017-04, ANR-10-LABX-62-IBEID), the Fondation pour la Recherche M?dicale FRM (DEQ20130326471), and the Institut Pasteur (PTR441). This study was also supported by the International Research & Development Program through the National Research Foundation of Korea?(NRF) funded by the Ministry of Science, ICT & Future Planning of?Korea?(NRF-2014K1A3A7A03075054). The mycobacterial construct BCG::ESX-1Mmar has been patented under number PCT/EP2015/062457.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)