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

Matthias I. Gröschel, Fadel Sayes, SungJae Shin, Wafa Frigui, Alexandre Pawlik, Mickael Orgeur, Robin Canetti, Nadine Honoré, Roxane Simeone, Tjip S. van der Werf, Wilbert Bitter, Sangnae Cho, Laleh Majlessi, Roland Brosch

Research output: Contribution to journalArticle

24 Citations (Scopus)

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-1Mmar confers superior protection relative to parental BCG against challenges with highly virulent M. tuberculosis.

Original languageEnglish
Pages (from-to)2752-2765
Number of pages14
JournalCell Reports
Volume18
Issue number11
DOIs
Publication statusPublished - 2017 Mar 14

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Mycobacterium marinum
Mycobacterium bovis
Virulence
Tuberculosis Vaccines
Inflammasomes
Antigens
Interferon Type I
Pattern recognition
Vaccines
Nucleotides
Sensors
Tuberculosis
Th1 Cells
Mycobacterium tuberculosis
Rupture
Vaccination

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Gröschel, Matthias I. ; Sayes, Fadel ; Shin, SungJae ; Frigui, Wafa ; Pawlik, Alexandre ; Orgeur, Mickael ; Canetti, Robin ; Honoré, Nadine ; Simeone, Roxane ; van der Werf, Tjip S. ; Bitter, Wilbert ; Cho, Sangnae ; Majlessi, Laleh ; Brosch, Roland. / Recombinant BCG Expressing ESX-1 of Mycobacterium marinum Combines Low Virulence with Cytosolic Immune Signaling and Improved TB Protection. In: Cell Reports. 2017 ; Vol. 18, No. 11. pp. 2752-2765.
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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-1Mmar confers superior protection relative to parental BCG against challenges with highly virulent M. tuberculosis.",
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Gröschel, MI, Sayes, F, Shin, S, Frigui, W, Pawlik, A, Orgeur, M, Canetti, R, Honoré, N, Simeone, R, van der Werf, TS, Bitter, W, Cho, S, Majlessi, L & Brosch, R 2017, 'Recombinant BCG Expressing ESX-1 of Mycobacterium marinum Combines Low Virulence with Cytosolic Immune Signaling and Improved TB Protection', Cell Reports, vol. 18, no. 11, pp. 2752-2765. https://doi.org/10.1016/j.celrep.2017.02.057

Recombinant BCG Expressing ESX-1 of Mycobacterium marinum Combines Low Virulence with Cytosolic Immune Signaling and Improved TB Protection. / Gröschel, Matthias I.; Sayes, Fadel; Shin, SungJae; Frigui, Wafa; Pawlik, Alexandre; Orgeur, Mickael; Canetti, Robin; Honoré, Nadine; Simeone, Roxane; van der Werf, Tjip S.; Bitter, Wilbert; Cho, Sangnae; Majlessi, Laleh; Brosch, Roland.

In: Cell Reports, Vol. 18, No. 11, 14.03.2017, p. 2752-2765.

Research output: Contribution to journalArticle

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AU - Gröschel, Matthias I.

AU - Sayes, Fadel

AU - Shin, SungJae

AU - Frigui, Wafa

AU - Pawlik, Alexandre

AU - Orgeur, Mickael

AU - Canetti, Robin

AU - Honoré, Nadine

AU - Simeone, Roxane

AU - van der Werf, Tjip S.

AU - Bitter, Wilbert

AU - Cho, Sangnae

AU - Majlessi, Laleh

AU - Brosch, Roland

PY - 2017/3/14

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N2 - 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.

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