Mycobacterium marinum causes a latent infection that can be reactivated by gamma irradiation in adult zebrafish

PLoS Pathog. 2012 Sep;8(9):e1002944. doi: 10.1371/journal.ppat.1002944. Epub 2012 Sep 27.

Abstract

The mechanisms leading to latency and reactivation of human tuberculosis are still unclear, mainly due to the lack of standardized animal models for latent mycobacterial infection. In this longitudinal study of the progression of a mycobacterial disease in adult zebrafish, we show that an experimental intraperitoneal infection with a low dose (≈ 35 bacteria) of Mycobacterium marinum, results in the development of a latent disease in most individuals. The infection is characterized by limited mortality (25%), stable bacterial loads 4 weeks following infection and constant numbers of highly organized granulomas in few target organs. The majority of bacteria are dormant during a latent mycobacterial infection in zebrafish, and can be activated by resuscitation promoting factor ex vivo. In 5-10% of tuberculosis cases in humans, the disease is reactivated usually as a consequence of immune suppression. In our model, we are able to show that reactivation can be efficiently induced in infected zebrafish by γ-irradiation that transiently depletes granulo/monocyte and lymphocyte pools, as determined by flow cytometry. This immunosuppression causes reactivation of the dormant mycobacterial population and a rapid outgrowth of bacteria, leading to 88% mortality in four weeks. In this study, the adult zebrafish presents itself as a unique non-mammalian vertebrate model for studying the development of latency, regulation of mycobacterial dormancy, as well as reactivation of latent or subclinical tuberculosis. The possibilities for screening for host and pathogen factors affecting the disease progression, and identifying novel therapeutic agents and vaccine targets make this established model especially attractive.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Disease Progression
  • Gamma Rays
  • Granulocytes / immunology
  • Granulocytes / radiation effects
  • Humans
  • Immunosuppression*
  • Lymphocytes / immunology
  • Lymphocytes / radiation effects
  • Monocytes / immunology
  • Monocytes / radiation effects
  • Mycobacterium Infections, Nontuberculous / immunology*
  • Mycobacterium Infections, Nontuberculous / microbiology*
  • Mycobacterium Infections, Nontuberculous / mortality
  • Mycobacterium marinum / physiology*
  • Tuberculosis / immunology
  • Tuberculosis / microbiology
  • Zebrafish*

Grant support

The study was financially supported by Academy of Finland (projects 128623, 135980, M. Pesu; 121003, M. Parikka; 139225, M. Rämet), a Marie Curie International Reintegration Grant within the 7th European Community Framework Programme (M. Pesu), Emil Aaltonen Foundation (M. Pesu), Sigrid Jusélius Foundation (M. Pesu, M. Rämet), Tampere Tuberculosis Foundation (M. Pesu, M. Parikka, M. Rämet), Finnish Anti-tuberculosis Foundation (M. Parikka, K. Oksanen, M. Hammarén, the Väinö and Laina Kivi Foundation (K. Oksanen) and Competitive Research Funding of the Tampere University Hospital (M. Pesu, M.Parikka and M. Rämet). The zebrafish work was carried out at University of Tampere core facility supported by Biocenter Finland, Tampere Tuberculosis Foundation and Emil Aaltonen Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.