Granulomas are organized structures that typically form during mycobacterial infections as a result of complex interactions between mycobacteria and the host. By the time that they are first detectable in mammals, granulomas contain both macrophages and T cells — so a longstanding puzzle has been whether granuloma formation is initiated by innate or adaptive immunity. Now, greater transparency (literally) has been provided by the zebrafish.

The embryos and early swimming larvae of zebrafish are optically transparent, making them an ideal model in which to observe pathogen–host interactions in real time. Adult zebrafish, which have both macrophages and T cells, can form granulomas in response to infection with Mycobacterium marinum, which is a close relative of the human pathogen Mycobacterium tuberculosis. But, do granulomas form in zebrafish embryos, at which stage only macrophages are present?

Muse Davis and co-workers injected zebrafish embryos intravenously with fluorescently labelled M. marinum then observed them by video microscopy. Three days later, infected macrophages could be seen to have extravasated into the tissues, and they had begun to aggregate — squeezing together to form clusters with the typical morphology of granulomas. Heat-killed M. marinum and Salmonella arizonae failed to induce the formation of such granuloma-like structures, which indicates that this process is triggered specifically by mycobacteria–host interactions.

To confirm that these were bona fide granulomas, the authors looked at the expression of M. marinum genes that had been characterized previously as being activated in granulomas (granuloma-activated genes, GAGs) or after infection of cultured macrophages (macrophage-activated genes, MAGs). All four MAGs of M. marinum were activated soon after phagocytosis by macrophages, but the three GAGs were activated only once the infected macrophages had aggregated. Therefore, the complex bacteria–host interactions that occur in adult granulomas are mimicked in the embryo.

So, it seems that innate immune factors are sufficient to initiate granuloma formation — which goes against previous studies that cast T cells in the leading role. This is the first time that pathogen–host interactions have been observed in vivo, as they happen. And this study establishes zebrafish embryos as an illuminating model in which to study granuloma formation.