A fresh look at mycobacterial pathogenicity with the zebrafish host model

Abstract

The zebrafish has earned its place among animal models to study tuberculosis and other infections caused by pathogenic mycobacteria. This model host is especially useful to study the role of granulomas, the inflammatory lesions characteristic of mycobacterial disease. The optically transparent zebrafish larvae provide a window on the initial stages of granuloma development in the context of innate immunity. Application of fluorescent dyes and transgenic markers enabled real-time visualization of how innate immune mechanisms, such as autophagy and inflammasomes, are activated in infected macrophages and how propagating calcium signals drive communication between macrophages during granuloma formation. A combination of imaging, genetic, and chemical approaches has revealed that the interplay between macrophages and mycobacteria is the main driver of tissue dissemination and granuloma development, while neutrophils have a protective function in early granulomas. Different chemokine signaling axes, conserved between humans and zebrafish, have been shown to recruit macrophages permissive to mycobacterial growth, control their microbicidal capacity, drive their spreading and aggregation, and mediate granuloma vascularization. Finally, zebrafish larvae are now exploited to explore cell death processes, emerging as crucial factors in granuloma expansion. In this review, we discuss recent advances in the understanding of mycobacterial pathogenesis contributed by zebrafish models.

Keywords: autophagy, cell death, chemokine signalling, granulomas, inflammasomes, macrophages, Mycobacterium, tuberculosis, zebrafish model.

FIGURE 1

Mycobacterial infection and granuloma formation in zebrafish larvae. After infection, Mycobacterium marinum is primarily phagocytosed by macrophages (1). Infected macrophages (2) undergo cell death (3). The release of cellular contents favors the recruitment of new cells that become infected (4) initiating the formation of primary granulomas (5) at the infection site. Egression of infected cells initiates the dissemination (6) of the infection through the blood circulation or tissues leading to the formation of secondary granulomas (7) in distant tissues. Granulomas undergo a maturation process (8) in which size and cell composition vary from primitive granulomas to early granulomas and necrotic granulomas. In adult zebrafish, granulomas contain additional immune cells such as T lymphocytes. Created with Biorender.com