University of Oulu

Luukinen, H., Hammarén, M., Vanha-aho, L., Svorjova, A., Kantanen, L., Järvinen, S., Luukinen, B., Dufour, E., Rämet, M., Hytönen, V., Parikka, M. (2017) Priming of innate antimycobacterial immunity by heat-killed Listeria monocytogenes induces sterilizing response in the adult zebrafish tuberculosis model. Disease Models and Mechanisms, 11 (1), dmm031658. doi:10.1242/dmm.031658

Priming of innate antimycobacterial immunity by heat-killed Listeria monocytogenes induces sterilizing response in the adult zebrafish tuberculosis model

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Author: Luukinen, Hanna1; Hammarén, Milka Marjut1; Vanha-aho, Leena-Maija1;
Organizations: 1Faculty of Medicine and Life Sciences, University of Tampere
2BioMediTech Institute, University of Tampere
3PEDEGO Research Unit, and Medical Research Center Oulu, University of Oulu
4Department of Children and Adolescents, Oulu University Hospital
5Fimlab Laboratories, Pirkanmaa Hospital District
6Oral and Maxillofacial Unit, Tampere University Hospital
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.5 MB)
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Language: English
Published: Company of Biologists, 2018
Publish Date: 2018-04-11


Mycobacterium tuberculosis remains one of the most problematic infectious agents, owing to its highly developed mechanisms to evade host immune responses combined with the increasing emergence of antibiotic resistance. Host-directed therapies aiming to optimize immune responses to improve bacterial eradication or to limit excessive inflammation are a new strategy for the treatment of tuberculosis. In this study, we have established a zebrafish-Mycobacterium marinum natural host-pathogen model system to study induced protective immune responses in mycobacterial infection. We show that priming adult zebrafish with heat-killed Listeria monocytogenes (HKLm) at 1 day prior to M. marinum infection leads to significantly decreased mycobacterial loads in the infected zebrafish. Using rag1−/− fish, we show that the protective immunity conferred by HKLm priming can be induced through innate immunity alone. At 24 h post-infection, HKLm priming leads to a significant increase in the expression levels of macrophage-expressed gene 1 (mpeg1), tumor necrosis factor α (tnfa) and nitric oxide synthase 2b (nos2b), whereas superoxide dismutase 2 (sod2) expression is downregulated, implying that HKLm priming increases the number of macrophages and boosts intracellular killing mechanisms. The protective effects of HKLm are abolished when the injected material is pretreated with nucleases or proteinase K. Importantly, HKLm priming significantly increases the frequency of clearance of M. marinum infection by evoking sterilizing immunity (25 vs 3.7%, P=0.0021). In this study, immune priming is successfully used to induce sterilizing immunity against mycobacterial infection. This model provides a promising new platform for elucidating the mechanisms underlying sterilizing immunity and to develop host-directed treatment or prevention strategies against tuberculosis.

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Series: Disease models & mechanisms
ISSN: 1754-8403
ISSN-E: 1754-8411
ISSN-L: 1754-8403
Volume: 11
Article number: dmm031658
DOI: 10.1242/dmm.031658
Type of Publication: A1 Journal article – refereed
Field of Science: 3141 Health care science
Funding: This work has been supported by the Finnish Cultural Foundation (H.L.), Tampere Tuberculosis Foundation (H.L., L.-M.V., M.M.H., B.V.L., M.R., M.P.), Foundation of the Finnish Anti-Tuberculosis Association (Suomen Tuberkuloosin Vastustamisyhdistyksen Säätiö) (H.L., M.M.H., B.V.L., M.P.), Sigrid Jusélius Foundation (M.P.), Emil Aaltonen Foundation (M.M.H.), Jane and Aatos Erkko Foundation (M.R.) and AFM-Téléthon (#17424, E.D.)
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.