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Furthermore, several pathogens inject virulence factors that promote actin polymerization to actively stimulate their uptake by both non-phagocytic and phagocytic cells Ogawa et al. Pathogens that are able to escape from the phagosome have mechanisms to evade autophagy and can spread from the initially infected cell to other cells by acquiring actin-based motility Ogawa et al. Other virulence mechanisms can induce inflammation and different cell-death programs to facilitate the dissemination of infection Hilbi et al.

These different virulence strategies are schematically depicted in Fig. Evasion of macrophage defense mechanisms by intracellular pathogens. Upon phagocytosis 1 , the pathogens generally reside within phagosomal compartments where a plethora of microbicidal components cooperate in a multidirectional assault to the microbes 2. By transferring virulence factors, often via secretion systems injectosomes , some pathogens can avoid the classical maturation steps of these compartments, creating a favorable niche for their intracellular growth 3, 4, 5.

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Several intracellular pathogens are able to escape directly into the cytosol 8. Here, septin cages 9 , galectin decoration 10 , ubiquitylation 11 and specific routes of antimicrobial autophagy 12 are activated to capture the escapers and redirect them to lytic compartments. Additionally, ubiquitylation of microbial proteins 11 labels these for proteasomal degradation Several intracellular pathogens can efficiently counteract this second line of intracellular defense and replicate freely within the cytosol 14 , frequently also manipulating the cell cytoskeleton 15 to sustain their extrusion and dissemination to other host cells Intracellular infections have profound influences also on a wide spectrum of host functions.

Cell signaling pathways can be manipulated to modulate the host inflammatory response 17 and control gene expression Some pathogens are also known to induce epigenetic modification of their host cells, leading to reprogramming Some virulence factors directly impact the homeostatic mechanisms by interfering with normal mitochondrial functionality 20 , membrane polarity and communication with the extracellular milieu The ultimate possibility for the host to eradicate the infection is to initiate cell pyroptotic, apoptotic or necroptotic suicide programs 20, 22, 23, However, the death mechanisms can also be modulated by pathogens, which can benefit from them by the induction of host damage, pathogen dissemination and the initiation of new replicative cycles.

The development of transgenic zebrafish lines with fluorescently labeled leukocytes supplementary material Table S1 has been key to the successful application of zebrafish for immunological studies. However, until recently, the lack of a specific reporter for the macrophage lineage limited the study of this myeloid subset. This has now been remedied with the development of the csf1ra and mpeg1 reporter lines Gray et al.

These genes are robust markers for macrophages at embryonic and larval stages, because they are co-expressed with the pan-leukocytic marker lcp1 but not with the neutrophil markers mpx and lyz Meijer et al. Despite the fact that csf1ra is macrophage-specific within the immune cell types, it is also expressed in neural crest cells and derivatives, such as the xanthophores.

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Nevertheless, the highly motile macrophages can be distinguished easily from the immobile xanthophores in time-course experiments Gray et al. Reporter lines using the mpeg1 promoter label macrophages but not xanthophores Fig. The mpeg1 reporter also labels microglia and it has been suggested to label other antigen-presenting cells, such as the Langerhans dendritic cells, but these could not be detected before 8—9 dpf Svahn et al.

In vivo imaging of macrophage responses to infection. Random patrolling of macrophages is shown in supplementary material Movie 1. B Phagocytosis of M. The arrow points at a macrophage red in the process of phagocytosis between 47 and 60 minutes post-infection. The images are particulars and stills from supplementary material Movie 2 10 to 60 minutes post-infection. C Macrophage-mediated dissemination of M.

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The white track represents the path of an infected macrophage migrating away from the infection focus. D Partial acidification of phagocytosed M. Bacteria double-labeled with constitutive mCrimson and pH-sensitive green pHrodo are contained within subcellular compartments of macrophages, which are intensely labeled by the membrane-bound mCherry of the Tg mpeg1:mCherry-F line. White arrows point at bacteria in acidified compartments, where the pHrodo dye is activated. Yellow arrows point at bacteria in non-acidified compartments. Note that most of the intracellular mycobacteria are not acidified, consistent with the ability of this pathogen to counteract phagosome maturation.

Macrophages were imaged in the yolk sac circulation valley 5 hours after injection of bacteria into the caudal vein at 2 dpf. Images in A—C were acquired with the Zeiss Observer 6. Figures and movies were processed with ImageJ. Expression of the Gal4 transcription factor under the control of macrophage or neutrophil promoters in combination with a UAS-nitroreductase-mCherry line allows for the specific ablation of one of the two phagocyte populations.

This approach can be used to investigate their individual contributions to the immune response and infectious disease pathogenesis Gray et al. Similarly, irf8 tools have also been used to deplete specific myeloid cell populations and to skew the development of their progenitors towards macrophages or neutrophils.

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Morpholino knockdown of irf8 can completely deplete macrophage differentiation while stimulating an increased output of neutrophils, and irf8 overexpression can direct myeloid development towards macrophage differentiation Li et al. Many other transgenic lines that label either the entire myeloid population, the early myeloid subset, microglia or all antigen-presenting cells are also very useful for the study of macrophage biology supplementary material Table S1.

Visualization of live macrophage behavior in zebrafish embryos can be achieved with great structural detail using digitally enhanced differential interference contrast DIC microscopy Herbomel et al. More recently, there has been tremendous progress in the use of transgenic marker lines supplementary material Table S1 and labeled pathogens that facilitate live imaging in spatial and temporal dimensions Fig. Photoconvertable fluorescent proteins such as Kaede and Dendra2 have been exploited to show that cells from the CHT can be recruited distally to infection foci and wounds Yoo et al.

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For imaging of phagocyte migration, pathogens or specific chemoattractants can be injected subcutaneously or into body cavities such as the otic vesicle and hindbrain ventricle, which can be reached without generating extensive tissue damage, thereby preventing wound-induced leukocyte mobilization Colucci-Guyon et al. To visualize phagocytosis and the intracellular fate of bacteria, the pHrodo dye can be conjugated to bioparticles or to live or heat-killed bacteria Fig. Furthermore, the nature of the compartments where the pathogens reside can be investigated with combinations of different vital stains, most of which are permeable into zebrafish embryos when added to the water.

Furthermore, an increasing number of transgenic marker lines for vesicular compartments are becoming available that will help in elucidating the subcellular locations where pathogens reside in vivo supplementary material Table S2. These lesions are histologically very similar to those generated by Mycobacterium tuberculosis , the etiological agent of human tuberculosis Prouty et al.

In adult zebrafish, M. Tuberculosis therapy is limited by a number of problems, including the poor response of dormant mycobacteria to antibiotics, the increasing prevalence of multidrug-resistant strains and the lack of an effective vaccine against latent or reactivated tuberculosis Ottenhoff and Kaufmann, The lack of a mouse model for tuberculosis that fully recapitulates the disease and the risk of working with the human pathogen owing to its airborne transmission emphasize the need for alternative models. The unique accessibility of the early stages of granuloma formation in zebrafish larvae has made the zebrafish- M.

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Notably, the use of this model has already provided several direct translational applications for human disease treatments Table 1. Models of intracellular infections in zebrafish. Schematic comparison of the infection phenotypes caused by different pathogens following intravenous injection in zebrafish embryos. Eventually the host macrophages succumb to the infection, and the pathogen spreads to new macrophages that have been recruited through bacterial virulence mechanisms.

This leads to the formation of granulomatous lesions. Occasionally, infected macrophages can egress from the primary granuloma and seed secondary granulomas. Upon replication, the pathogen induces pyroptotic cell death. Extracellular Salmonella continues to replicate. Additionally, it can be non-lytically expelled from the host macrophages. Within the extracellular environment, the pathogen stimulates leukocyte aggregation and continues replication. The resulting uncontrolled bacteremia is the major cause of the fatal complications. By contrast, when phagocytosed by neutrophils, most of the pathogen can be efficiently neutralized.

However, resistant clones occasionally emerge and expand within these cells. Within these cells the pathogen escapes immediately into the cytosol and gains actin-based motility, by which it disseminates from cell to cell. Within macrophages, the pathogen can also escape from the phagosome, but here a more efficient cytosolic control partially combats the invader, delaying although not avoiding macrophage cell death. Neutrophils represent efficient scavengers for extracellular Shigella released from dying epithelial cells and macrophages but the infection is still rapidly lethal.

F Phagocytosis of C. The fungus can still slowly replicate and eventually is released. Extracellularly, the yeast can germinate and the resulting fast-replicating hyphae will invade the whole organism, leading to systemic infection. Therapeutic strategies inspired by the zebrafish model to counteract intracellular infections. Infection of zebrafish embryos with M. Subsequently, this model changed the widespread view of granulomas, historically regarded solely as host-protective structures, by showing that early granulomas promote mycobacterial dissemination Fig.

Furthermore, the ESXsecreted protein ESAT-6 Early secreted antigenic target 6 was found to induce matrix metalloproteinase Mmp9 production by epithelial cells surrounding the infection focus, which in turn facilitates macrophage infiltration. As a result, the application of Mmp9 antagonists has been suggested as a host-directed anti-tuberculosis therapy Volkman et al.

The notion that granulomas are dynamic structures, even during latent infection, is supported by a study of M. Mycobacteria are well known for developing drug tolerance. The zebrafish embryo model has demonstrated that their intramacrophage localization correlates with development of resistance and that granulomas promote dissemination of this resistant population.

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Upregulation of bacterial efflux pumps, which are required for intracellular growth, can mediate drug tolerance both in M. Efflux-pump inhibitors, already available on the market, can reduce this tolerance, and their addition to standard anti-tuberculosis therapy might therefore shorten treatment duration Adams et al. Another important insight into tuberculosis pathogenesis concerns the relevance of the inflammatory status. A zebrafish mutagenesis screen revealed Lta4h Leukotriene A 4 hydrolase as a host factor that strongly correlates with M. This enzyme is required for producing LTB 4 Leukotriene B 4 , a powerful proinflammatory chemoattractant.

Lta4h deficiency correlates with a less inflamed status, due to redirection of its substrates to anti-inflammatory lipoxins, resulting in reduced levels of proinflammatory cytokines such as tumor necrosis factor TNF. The crucial role of TNF in controlling mycobacterial infection is exemplified by the increased risk of tuberculosis in patients with chronic inflammatory disorders treated with TNF antagonists Wallis, However, excessive production of TNF is also associated with higher susceptibility to tuberculosis.

This has been shown in zebrafish and other animal models as well as in tuberculosis meningitis patients, where a polymorphism at the LTA4H locus that causes increased TNF production has been linked with more progressive disease symptoms Tsenova et al.