Recombinant BCG Expressing ESX-1 of Mycobacterium marinum Combines Low Virulence with Cytosolic Immune Signaling and Improved TB Protection
Open accessAbstract
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. tuberculosi s.
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Several recombinant BCG vaccine candidates have been constructed to overcome these limitations of BCG.
“Several recombinant BCG vaccine candidates have been constructed to overcome these limitations of BCG (75,(87)(88)(89)(90).”
From ESX/Type VII Secretion Systems—An Important Way Out for Mycobacterial Proteins (2019) · cites this paper as [75]
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References 75 · Cited by 125
Research works printed but not linked: 2
- Dorhoi, A., Nouailles, G., Jo ¨ rg, S., Hagens, K., Heinemann, E., Pradl, L., Oberbeck-M € uller, D., Duque-Correa, M.A., Reece, S.T., Ruland, J., et al. (2012). ActivationoftheNLRP3inflammasomeby Mycobacteriumtuberculosis is uncoupled from susceptibility to active tuberculosis. Eur. J. Immunol. 42 , 374-384. http://refhub.elsevier.com/S2211-1247(1730255-3/sref19)
- Watson, R.O., Bell, S.L., MacDuff, D.A., Kimmey, J.M., Diner, E.J., Olivas, J., Vance, R.E., Stallings, C.L., Virgin, H.W., and Cox, J.S. (2015). The Cytosolic Sensor cGAS Detects Mycobacterium tuberculosis DNAtoInduceTypeIInterferons and Activate Autophagy. Cell Host Microbe 17 , 811-819. http://refhub.elsevier.com/S2211-1247(1730255-3/sref72)
- Authors
- 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.
- Affiliations
- University Medical Center Groningen (NL)
- Institut Pasteur (FR)
- Yonsei University (KR)
- Vrije Universiteit Amsterdam (NL)
- Corresponding author
- Brosch, Roland
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 18
- Issue
- 11
- Pages
- 2752-2765
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2597394874
- Cited by
- 125
- References
- 75
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 11 · 2023: 2 · 2022: 15 · 2021: 18 · 2020: 19 · 2019: 17 · 2018: 11 · 2017: 8
- FWCI
- 11.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by-nc-nd)
- VU Research Portal (publishedVersion, other-oa)
- HAL (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc-nd)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Horizon 2020 (643381 TBVAC2020)
- Agence Nationale de la Recherche (ANR-10-LABX-62-IBEID, ANR-14-CE-08-0017-04, ANR-14-JAMR-001-02)
- Fondation pour la Recherche Médicale (DEQ20130326471)
- National Research Foundation of Korea
- Institut Pasteur (PTR441)
- Technische Universität München (CFP-10)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- recombinant BCG, type VII secretion system, Mycobacterium tuberculosis, tuberculosis vaccine, type I interferon, AIM2 inflammasome, NLRP3 inflammasome, CD8+ T cell responses, Th1 cells, vaccine virulence
- MeSH terms
- Animals, Bacterial Proteins, BCG Vaccine, Cytosol, Genetic Complementation Test, Immunity, Innate, Immunization, Phagosomes, Tuberculosis, Vaccines, Synthetic, Virulence, Signal Transduction, Mice, SCID, Th1 Cells, Mycobacterium marinum, Host-Pathogen Interactions
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