Journal
CELL REPORTS
Volume 18, Issue 11, Pages 2752-2765Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.02.057
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Funding
- MD/PhD
- Graduate School of Medical Sciences
- University of Groningen
- Netherlands
- European Union's Horizon Research and Innovation Program [643381 TBVAC2020]
- Agence National de Recherche [ANR-14-JAMR001-02, ANR-14-CE-08-0017-04, ANR-10-LABX-62-IBEID]
- Fondation pour la Recherche Medicale FRM [DEQ20130326471]
- Institut Pasteur [PTR441]
- International Research & Development Program through the National Research Foundation of Korea (NRF) - Ministry of Scienc, ICT & Future Planning of Korea [NRF-2014K1A3A7A03075054]
- [PCT/EP2015/062457]
- National Research Foundation of Korea [2014K1A3A7A03075054] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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, Mycobacteriumbovis 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 intracellularphenotypes linked toincreased 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 virulentM. tuberculosis.
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