This review discusses how research in zebrafish 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.
Meijer AH (2015) Protection and pathology in TB: learning from the zebrafish model. Semin Immunopathol, in press
This review discusses recent advances in our understanding of hypoxia and HIFs in disease that have emerged from studies of zebrafish models.
Elks PM, Renshaw SA, Meijer AH, Walmsley S and van Eeden FJ (2015) Exploring the HIFs, buts and maybes of hypoxia signalling in disease: lessons from zebrafish models. Dis. Model Mech 8: 1349-1360
In this study, the authors identify two zebrafish orthologues of the transcription factor Promyelocytic Leukemia Zinc Finger (PLZF, or ZBTB16), and show they have distinct expression patterns. This study indicates that the over-expression of Plzf increases the level of the early type I IFN response, at a critical phase in the race between the virus and the host response. Thus, Plzf implication in the regulation of type I IFN responses is conserved across vertebrates, but through different mechanisms.
Aleksejeva E., Houel A., Briolat V., Levraud J.-P., Langevin C., Boudinot P. Dev Comp Immunol. 2015 Dec 21. pii: S0145-305X(15)30099-9. doi: 10.1016/j.dci.2015.12.016. [pub ahead of print]
In this study, the authors characterized the transcriptional responses of zebrafish embryos to injection of Pam3CSK4 and flagellin, Tlr2 and Tlr5 specific ligands. These results showed that both signaling pathways are conserved in between zebrafish and mammals and revealed a set of specific genes that could be further studied and used as a potential target for the treatment of different infectious diseases (e.g. Tuberculosis).
Yang S, Marín-Juez R, Meijer AH, Spaink HP. Common and specific downstream signaling targets controlled by Tlr2 and Tlr5 innate immune signaling in zebrafish. BMC Genomics. 2015 Jul 25;16:547. doi: 10.1186/s12864-015-1740-9.
This in vivo imaging study in medaka fish larvae shows that the expression of two chemokine receptors in the juvenile thymus defines two spatially distinct subpopulations of thymocytes. The study also shows that the migratory behavior of thymocytes is partly correlated with their developmental stage rather than being defined by their spatial localization.
Bajoghli B, Kuri P, Inoue D, Aghaallaei N, Hanelt M, Thumberger T, Rauzi M, Wittbrodt J, Leptin M. (2015) Noninvasive In Toto Imaging of the Thymus Reveals Heterogeneous Migratory Behavior of Developing T Cells. J Immunol 195: 2177-86
For the first time in this study the dynamics of macrophage polarization is shown in live vertebrates. By generating a double transgenic zebrafish line that contains a macrophage marker (mpeg1:mCherry-F) and a reporter for classical activation (M1) of macrophages (TNFa:eGFP-F) it could be shown that a subset of macrophages polarizes towards an M1 phenotype in response to wounding or infection (as hown in the figure). Fate tracing showed that these activated macrophages converted into M2-like phenotype during the resolution step.
Nguyen-Chi M, Laplace-Builhe B, Travnickova J, Luz-Crawford p, Tejedor G, Phan Q-T, Doroux-Richard I, Levraud J-P, Kissa K, Lutfalla G, Jorgensen C, Djouad F. Identification of polarized macrophage subsets in zebrafish. Elife. 2015 4:e07288
In vertebrates, Hematopoietic Stem/ProgenitorCells (HSPCs) emerge from endothelial cells of the ventral wall of the dorsal aorta in the AGM region (Aorta-Gonad-Mesonephros). While they ultimately join the blood flow to colonize hematopoietic organs, they bud from the aorta endothelium inside the tissue between the aorta and the vein. They travel within this tissue and ultimately reach the vein where they intravasate the blood flow. We show here that macrophages play a critical role in secreting MMPs to degrade the Extra Cellular Matrix (ECM) between the aorta and the vein to allow HSPCs migration from the floor of the aorta to the vein. The image shows an red fluorescent Macrophage patrolling around a green fluorescent HSPC, releasing MMPs to degrade the ECM.
Travnickova J, Tran Chau V, Julien E, Mateos-Langerak J, Gonzalez C, Lelievre E, Lutfalla G, Tavian M, Kissa K. Nat Commun. 2015 Feb 17;6:6227. doi:10.1038/ncomms7227. PMID: 25686881 [PubMed - in process]
In this study, the authors identify zebrafish Md1 and Rp105 and show that their genetic inhibition results in impaired expression of genes encoding pro-inflammatory and antiviral molecules, leading to increased susceptibility to viral infection. These results shed light on the evolutionary history of Md1 and Rp105 and uncover a previously unappreciated function of these molecules in the regulation of innate immunity.
Candel S, Sepulcre MP, Espin-Palazon R, Tyrkalska SD, de Oliveira S, Meseguer J, MuleroV. Dev Comp Immunol. 2015 Feb 11. pii: SO145-305X(15)00012-9. doi:10.1016/j.dci.2015.01.005. [Epub ahead of print]
In this study, the authors used a zebrafish model of tuberculosis to show that mutation of a zebrafish CXCR3 homolog attenuates the infection-dependent recruitment of macrophages and limits the dissemination of the pathogen via macrophage carriers. The results suggests that the CXCR3/CXCL11 signaling axis might represent a host-directed therapeutic target for treatment of tuberculosis.
Torraca V, Cui C, Boland R, Bebelman JP, van der Sar AM, Smit MJ, Siderius M, Spaink HP, Meijer AH. Dis Model Mech. 2015 Jan 8. pii: dmm.017756.
This improved zebrafish larvae drug screening platform offers new insights into drug efficacy and identifies potential false negatives and drugs that are effective in zebrafish and rodents. Thereby this platform can complement conventional models of in vivo rodent assays. The detailed comparison of fish and rodent may give more predictive value for efficacy of drugs in humans.
Ordas A, Raterink RJ, Cunningham F, Jansen HJ, Wiweger MI, Jong-Raadsen S, Bates RH, Barros D, Meijer AH, Vreeken RJ, Ballell-Pages L, Dirks RP, Hankemeier T, Spaink HP. Testing tuberculosis drug efficacy in a zebrafish high-throughput translational medicine screen. Antimicrob Agents Chemother. 2014 Nov 10. pii: AAC.03588-14.