University of Oulu

Myllymäki, H., Niskanen, M., Luukinen, H., Parikka, M., & Rämet, M. (2018). Identification of protective postexposure mycobacterial vaccine antigens using an immunosuppression-based reactivation model in the zebrafish. Disease Models & Mechanisms, 11(3), dmm033175.

Identification of protective postexposure mycobacterial vaccine antigens using an immunosuppression-based reactivation model in the zebrafish

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Author: Myllymäki, Henna1; Niskanen, Mirja1; Luukinen, Hanna1;
Organizations: 1BioMediTech Institute and Faculty of Medical and Life Sciences, University of Tampere, Tampere FI-33014, Finland
2Oral and Maxillofacial Unit, Tampere University Hospital, Tampere FI-33521, Finland
3Department of Pediatrics, Tampere University Hospital, Tampere FI-33521, Finland
4Department of Children and Adolescents, Oulu University Hospital, Oulu FI-90220, Finland
5PEDEGO Research Unit, and, Medical Research Center, University of Oulu, Oulu FI-90014, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.8 MB)
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Language: English
Published: Company of Biologists, 2018
Publish Date: 2019-06-24


Roughly one third of the human population carries a latent Mycobacterium tuberculosis infection, with a 5–10% lifetime risk of reactivation to active tuberculosis and further spreading the disease. The mechanisms leading to the reactivation of a latent Mycobacterium tuberculosis infection are insufficiently understood. Here, we used a natural fish pathogen, Mycobacterium marinum, to model the reactivation of a mycobacterial infection in the adult zebrafish (Danio rerio). A low-dose intraperitoneal injection (∼40 colony-forming units) led to a latent infection, with mycobacteria found in well-organized granulomas surrounded by a thick layer of fibrous tissue. A latent infection could be reactivated by oral dexamethasone treatment, which led to disruption of the granuloma structures and dissemination of bacteria. This was associated with the depletion of lymphocytes, especially CD4⁺ T cells. Using this model, we verified that ethambutol is effective against an active disease but not a latent infection. In addition, we screened 15 mycobacterial antigens as postexposure DNA vaccines, of which RpfB and MMAR_4207 reduced bacterial burdens upon reactivation, as did the Ag85-ESAT-6 combination. In conclusion, the adult zebrafish-M. marinum infection model provides a feasible tool for examining the mechanisms of reactivation in mycobacterial infections, and for screening vaccine and drug candidates.

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Series: Disease models & mechanisms
ISSN: 1754-8403
ISSN-E: 1754-8411
ISSN-L: 1754-8403
Volume: 11
Issue: 3
Article number: UNSP dmm033175
DOI: 10.1242/dmm.033175
Type of Publication: A1 Journal article – refereed
Field of Science: 3142 Public health care science, environmental and occupational health
Funding: This work was supported by Jane ja Aatos Erkon Säätiö (Jane and Aatos Erkko Foundation; to M.R.), Sigrid Juséliuksen Säätiö (Sigrid Juselius Foundation; to M.R. and M.P.), the Competitive State Research Financing of the Expert Responsibility area of Tampere University Hospital (to M.R.), Tampereen Tuberkuloosisäätiö (Tampere Tuberculosis Foundation; to M.R., M.P., H.M., M.N. and H.L.), Suomen Kulttuurirahasto (Finnish Cultural Foundation; to H.M. and H.L.), Suomen Tuberkuloosin Vastustamisyhdistyksen Säätiö (Finnish Anti-Tuberculosis Foundation; to H.M. and H.L.), Väinö ja Laina Kiven säätiö (Väinö and Laina Kivi Foundation; to M.N.) and the Tampere City Science Foundation (to M.N.).
Copyright information: © 2018. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.