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Dis Model Mech. 2018 Jan 29;11(1). pii: 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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Faculty of Medicine and Life Sciences, FI-33014 University of Tampere, Tampere, Finland.
Faculty of Medicine and Life Sciences, FI-33014 University of Tampere, Tampere, Finland
BioMediTech Institute, FI-33014 University of Tampere, Tampere, Finland.
PEDEGO Research Unit, and Medical Research Center Oulu, FI-90014 University of Oulu, Oulu, Finland.
Department of Children and Adolescents, Oulu University Hospital, FI-90220 Oulu, Finland.
Fimlab Laboratories, Pirkanmaa Hospital District, FI-33520 Tampere, Finland.
Oral and Maxillofacial Unit, Tampere University Hospital, FI-33521 Tampere, Finland.


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.This article has an associated First Person interview with the first author of the paper.


Listeria monocytogenes; Mycobacterial infection; Mycobacterium marinum; Sterilizing immunity; Tuberculosis; Zebrafish

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