Macrophage-Microbe Interactions: Lessons from the Zebrafish Model

Abstract

Macrophages provide front line defense against infections. The study of macrophage-microbe interplay is thus crucial for understanding pathogenesis and infection control. Zebrafish (Danio rerio) larvae provide a unique platform to study macrophage-microbe interactions in vivo, from the level of the single cell to the whole organism. Studies using zebrafish allow non-invasive, real-time visualization of macrophage recruitment and phagocytosis. Furthermore, the chemical and genetic tractability of zebrafish has been central to decipher the complex role of macrophages during infection. Here, we discuss the latest developments using zebrafish models of bacterial and fungal infection. We also review novel aspects of macrophage biology revealed by zebrafish, which can potentiate development of new therapeutic strategies for humans.

Keywords: host–pathogen interactions; infection; inflammation; macrophage; zebrafish.

Figure 1

Zebrafish macrophage-microbe interactions in vivo. (A) Differential interference contrast (left) and fluorescent microscopy (right) image of macrophage aggregation to Mycobacterium marinum in the tail of wild-type AB larvae. Asterisk (*) indicates an infected macrophage at the aggregate; arrows indicate infected macrophages near the aggregate. m, melanocyte; s, striated muscle; scale bar 25 µm. Image adapted from Ref. (42). (B) Electron microscopy images of the caudal hematopoietic tissue of wild-type AB larvae injected intravenously with Listeria monocytogenes 3 h postinfection (hpi). Listeria in a macrophage cytosol (arrowheads; top image), and Listeria in a macrophage phagosome (bottom image). Scale bar 1 µm. Images adapted from Ref. (53). (C) Confocal time-lapse images of Tg(mpeg1:G/U:nfsb-mCherry) larva (red macrophages) infected with Shigella flexneri (green) by caudal vein injection, first frame at 20 min postinjection (mpi). White arrow depicts GFP-Shigella phagocytosed by a red macrophage, with a loss of red fluorescence at frame 01:56 indicating macrophage cell death. Maximum intensity projection of six planes every 2 µm, scale bar 10 µm. Images adapted from Ref. (54). (D) High content imaging of Tg(fms:Gal4.VP16)il86; Tg(UAS:nfsb.mCherry)il49 larvae harboring macrophages (middle) injected with Cryptococcus neoformans (top) into the yolk sac circulation valley; bottom panel showing a merged image of both macrophages (magenta) and C. neoformans (green). Maximum intensity projection of images obtained 2hpi. Images adapted from Ref. (55). (E) Hindbrain ventricle injection of viable (top row) or non-viable (bottom row) Mucor circinelloides spores (cyan) in Tg(mpeg1:G/U:nfsb-mCherry/mpx:GFP) larvae harboring red macrophages imaged at 10 h 45 min and 1 h 5 min, respectively. Asterisks (*) indicate spores inside macrophages (red). Z-stack of 15 sections every 7.3 µm; scale bar 20 µm. Images adapted from Ref. (56). All adapted images were used with the appropriate permissions from the copyright holders of this work.