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

doi: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

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^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	2752-2765
Number of pages	14
Journal	Cell Reports
Volume	18
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2017.02.057
Publication status	Published - 14 Mar 2017

Funding

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 Médicale 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.

Funders	Funder number
Graduate School of Medical Sciences, both University of Groningen
Ministry of Science, ICT & Future Planning of Korea	NRF-2014K1A3A7A03075054, PCT/EP2015/062457
Horizon 2020 Framework Programme
Agence Nationale de la Recherche	ANR-10-LABX-62-IBEID, ANR-14-JAMR-001-02, ANR-14-CE-08-0017-04
Fondation pour la Recherche Médicale	DEQ20130326471
National Research Foundation of Korea
Institut Pasteur	PTR441
Technische Universität München	CFP-10
Horizon 2020	643381

Keywords

cytosolic pattern recognition
ESX/type VII secretion
innate immune signaling
Mycobacterium marinum
Mycobacterium tuberculosis
recombinant BCG
tuberculosis
vaccination

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Gröschel, M. I., Sayes, F., Shin, S. J., Frigui, W., Pawlik, A., Orgeur, M., Canetti, R., Honoré, N., Simeone, R., van der Werf, T. S., Bitter, W., Cho, S. N., 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, 18(11), 2752-2765. https://doi.org/10.1016/j.celrep.2017.02.057

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

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, 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 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

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AU - Gröschel, Matthias I.

AU - Sayes, Fadel

AU - Shin, Sung Jae

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, Sang Nae

AU - Majlessi, Laleh

AU - Brosch, Roland

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AB - 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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KW - ESX/type VII secretion

KW - innate immune signaling

KW - Mycobacterium marinum

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KW - recombinant BCG

KW - tuberculosis

KW - vaccination

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

Abstract

Funding

Keywords

UN SDGs

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