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 Honore; 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 Honore, Roxane Simeone, Tjip S. van der Werf, Wilbert Bitter, Sang-Nae Cho, Laleh Majlessi, Roland Brosch^*

^*Corresponding author for this work

Microbes in Health and Disease (MHD)

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

94 Citations (Scopus)

342 Downloads (Pure)

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, 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.

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

Keywords

TUBERCULOSIS INFECTION
VII SECRETION
INFLAMMASOME ACTIVATION
ENHANCED PROTECTION
MICROTI VACCINE
CALMETTE-GUERIN
I INTERFERONS
BOVIS BCG
HOST DNA
CELLS

Access to Document

10.1016/j.celrep.2017.02.057Licence: CC BY-NC-ND

Recombinant BCG Expressing ESX-1 of Mycobacterium marinum Combines Low Virulence with Cytosolic Immune Signaling and Improved TB ProtectionFinal publisher's version, 4.74 MBLicence: CC BY-NC-ND

Handle.net

Persistent link

Cite this

Gröschel, M. I., Sayes, F., Shin, S. J., Frigui, W., Pawlik, A., Orgeur, M., Canetti, R., Honore, 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

@article{b6aff249796b4a08bdf31c3312f49026,

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, 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.",

keywords = "TUBERCULOSIS INFECTION, VII SECRETION, INFLAMMASOME ACTIVATION, ENHANCED PROTECTION, MICROTI VACCINE, CALMETTE-GUERIN, I INTERFERONS, BOVIS BCG, HOST DNA, CELLS",

author = "Gr{\"o}schel, {Matthias I.} and Fadel Sayes and Shin, {Sung Jae} and Wafa Frigui and Alexandre Pawlik and Mickael Orgeur and Robin Canetti and Nadine Honore and Roxane Simeone and {van der Werf}, {Tjip S.} and Wilbert Bitter and Sang-Nae Cho and Laleh Majlessi and Roland Brosch",

year = "2017",

month = mar,

day = "14",

doi = "10.1016/j.celrep.2017.02.057",

language = "English",

volume = "18",

pages = "2752--2765",

journal = "Cell reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "11",

}

Gröschel, MI, Sayes, F, Shin, SJ, Frigui, W, Pawlik, A, Orgeur, M, Canetti, R, Honore, N, Simeone, R, van der Werf, TS, 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, vol. 18, no. 11, pp. 2752-2765. https://doi.org/10.1016/j.celrep.2017.02.057

TY - JOUR

T1 - Recombinant BCG Expressing ESX-1 of Mycobacterium marinum Combines Low Virulence with Cytosolic Immune Signaling and Improved TB Protection

AU - Gröschel, Matthias I.

AU - Sayes, Fadel

AU - Shin, Sung Jae

AU - Frigui, Wafa

AU - Pawlik, Alexandre

AU - Orgeur, Mickael

AU - Canetti, Robin

AU - Honore, Nadine

AU - Simeone, Roxane

AU - van der Werf, Tjip S.

AU - Bitter, Wilbert

AU - Cho, Sang-Nae

AU - Majlessi, Laleh

AU - Brosch, Roland

PY - 2017/3/14

Y1 - 2017/3/14

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, 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.

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, 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.

KW - TUBERCULOSIS INFECTION

KW - VII SECRETION

KW - INFLAMMASOME ACTIVATION

KW - ENHANCED PROTECTION

KW - MICROTI VACCINE

KW - CALMETTE-GUERIN

KW - I INTERFERONS

KW - BOVIS BCG

KW - HOST DNA

KW - CELLS

U2 - 10.1016/j.celrep.2017.02.057

DO - 10.1016/j.celrep.2017.02.057

M3 - Article

C2 - 28297677

SN - 2211-1247

VL - 18

SP - 2752

EP - 2765

JO - Cell reports

JF - Cell reports

IS - 11

ER -

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

Abstract

Keywords

Access to Document

Handle.net

Fingerprint

Cite this