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

Recombinant BCG Expressing ESX-1 of Mycobacterium marinum Combines Low Virulence with Cytosolic Immune Signaling and Improved TB Protection.
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Gröschel MI, Sayes F, Shin SJ, Frigui W, Pawlik A, Orgeur M, Canetti R, Honoré N, Simeone R, van der Werf TS, Bitter W, Cho SN, Majlessi L, Brosch R,


Gröschel MI, Sayes F, Shin SJ, Frigui W, Pawlik A, Orgeur M, Canetti R, Honoré N, Simeone R, van der Werf TS, Bitter W, Cho SN, Majlessi L, Brosch R, (click to view)

Gröschel MI, Sayes F, Shin SJ, Frigui W, Pawlik A, Orgeur M, Canetti R, Honoré N, Simeone R, van der Werf TS, Bitter W, Cho SN, Majlessi L, Brosch R,

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Cell reports 18(11) 2752-2765 pii 10.1016/j.celrep.2017.02.057

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-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.

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