Protection and pathology in TB: learning from the zebrafish model.

Annemarie H Meijer

doi:10.1007/s00281-015-0522-4

Abstract

Zebrafish has earned its place among animal models of tuberculosis. Its natural pathogen, Mycobacterium marinum, shares major virulence factors with the human pathogen Mycobacterium tuberculosis. In adult zebrafish, which possess recombination-activated adaptive immunity, it can cause acute infection or a chronic progressive disease with containment of mycobacteria in well-structured, caseating granulomas. In addition, a low-dose model that closely mimics human latent infection has recently been developed. These models are used alongside infection of optically transparent zebrafish embryos and larvae that rely on innate immunity and permit non-invasive visualization of the early stages of developing granulomas that are inaccessible in other animal models. By microinjecting mycobacteria intravenously or into different tissues, systemic and localized infections can be induced, each useful for studying particular aspects of early pathogenesis, such as phagocyte recruitment, granuloma expansion and maintenance, vascularization of granulomas, and the phagocyte-mediated dissemination of mycobacteria. This has contributed to new insights into the mycobacteria-driven mechanisms that promote granuloma formation, the double-edged role of inflammation, the mechanisms of macrophage cell death that favor disease progression, and the host-protective role of autophagy. As a result, zebrafish models are now increasingly used to explore strategies for adjunctive therapy of tuberculosis with host-directed drugs.

Highlights

Mycobacterium tuberculosis (Mtb) is one of the most successful human pathogens that is estimated to have infected one third of the human population and to be responsible for nine million new cases of tuberculosis (TB) in 2013 (WHO Global Tuberculosis report 2014)
The main strength of the zebrafish model for TB research is the optical access in embryos and larvae to the early stages of granulomas that develop in the context of innate immunity
The ease of genetic and pharmacological manipulation in embryos and larvae has helped to gain better understanding of the roles of macrophages and neutrophils in early pathogenesis and has revealed molecular mechanisms that are exploited by virulent mycobacteria to promote their expansion and dissemination inside the infected host

Summary

Introduction

Mycobacterium tuberculosis (Mtb) is one of the most successful human pathogens that is estimated to have infected one third of the human population and to be responsible for nine million new cases of tuberculosis (TB) in 2013 (WHO Global Tuberculosis report 2014). This means that the early stages of granuloma formation can be observed in optically transparent zebrafish embryos and larvae that have a functional innate immune system but have not yet developed adaptive immunity. This review will discuss how studies either in adult zebrafish or in embryos and larvae have advanced our understanding of mycobacterial virulence factors and of host genes implicated in immune protection or TB pathogenesis.

Results

Conclusion