<i>Pseudomonas aeruginosa</i>Type III secretion system interacts with phagocytes to modulate systemic infection of zebrafish embryos

Brannon, Mark K.; Davis, J. Muse; Mathias, Jonathan R.; Hall, Cathy W.; Emerson, Julia; Crosier, Philip S.; Huttenlocher, Anna; Ramakrishnan, Lalita; Moskowitz, Samuel M.

doi:10.1111/j.1462-5822.2009.01288.x

Cited by 121 publications

(161 citation statements)

References 62 publications

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“…15 However, subsequent reports have suggested that the transgene becomes restricted to neutrophils after 2 dpf. 43 In support of these findings, we show herein that mononuclear phagocytes do not express lyz transcripts and that the expression of mhc2dab:GFP is mutually exclusive to lyz:DsRed in the adult kidney. Finally, because our transgenic lines allow for the distinction between macrophages and neutrophils, we have investigated the expression of several genes recently reported to be macrophage specific in the zebrafish embryo.…”

Section: Discussionsupporting

confidence: 70%

Characterization of the mononuclear phagocyte system in zebrafish

Wittamer

Gutschow

Traver

2011

Blood

187

180

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The evolutionarily conserved immune system of the zebrafish (Danio rerio), in combination with its genetic tractability, position it as an excellent model system in which to elucidate the origin and function of vertebrate immune cells. We recently reported the existence of antigenpresenting mononuclear phagocytes in zebrafish, namely macrophages and dendritic cells (DCs), but have been impaired in further characterizing the biology of these cells by the lack of a specific transgenic reporter line. Using regulatory elements of a class II major histocompatibility gene, we generated a zebrafish reporter line expressing green fluorescent protein (GFP) in all APCs, macrophages, DCs, and B lymphocytes. Examination of mhc2dab:GFP; cd45:DsRed doubletransgenic animals demonstrated that kidney mhc2dab:GFP hi ; cd45:DsRed hi cells were exclusively mature monocytes/macrophages and DCs, as revealed by morphologic and molecular analyses. Mononuclear phagocytes were found in all hematolymphoid organs, but were most abundant in the intestine and spleen, where they up-regulate the expression of inflammatory cytokines upon bacterial challenge. Finally, mhc2dab:GFP and cd45:DsRed transgenes mark mutually exclusive cell subsets in the lymphoid fraction, enabling the delineation of the major hematopoietic lineages in the adult zebrafish. These findings suggest that mhc2dab:GFP and cd45:DsRed transgenic lines will be instrumental in elucidating the immune response in the zebrafish. (Blood. 2011;117(26):7126-7135) IntroductionIn recent years, the zebrafish (Danio rerio) has proven to be a unique vertebrate model for the study of hematopoiesis. 1 The use of the zebrafish to study the ontogeny of leukocyte subsets, 2 immune cell migration, 3,4 and host-pathogen interactions 5 has provided new insights into our understanding of innate immunity in the developing vertebrate embryo. A major focus of previous studies was on the neutrophil response, because several transgenic reporter lines have been generated that mark this granulocyte subset. Whereas neutrophils generally constitute the first line of defense against invading pathogens, the role of other immune cell subsets in the innate immune response has received less attention. In addition to neutrophils, macrophages are key in the response to pathogen challenge. In the zebrafish embryo, primitive macrophages have been demonstrated to be capable of clearing injected bacteria by phagocytosis. 6 However, the absence of markers specific to macrophages has limited the study of this myeloid cell subset in the zebrafish.The mononuclear phagocyte system (MPS) comprises monocytes, tissue macrophages, and dendritic cells (DCs), as well as their lineage-committed progenitors. 7 The primary function of mature MPS cells is the clearance of pathogens by phagocytosis. This activity is crucial during immune challenge to clear invasive pathogens. Mononuclear phagocytes also play an important role in the removal of apoptotic cell corpses, especially during embryonic development. In mice, embryonic macrop...

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Section: Discussionsupporting

confidence: 70%

Characterization of the mononuclear phagocyte system in zebrafish

Wittamer

Gutschow

Traver

2011

Blood

187

180

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“…KinB regulates pyocyanin and elastase production. It has previously been shown that both quorum sensing and T3S are required for P. aeruginosa infection of zebrafish embryos at 50 hpf, similar to rodent models of acute P. aeruginosa infection (6,9). Thus, since PA14⌬kinB was attenuated in fish, we ex- Since clutch size limits the number of mutants that can be examined in each experiment and the 100% lethal dose (LD 100 ) of P. aeruginosa can vary between different embryo clutches, whether a mutant is attenuated or not is determined with reference to infection with the wild-type PA14 strain within the same embryo clutch.…”

Section: Resultsmentioning

confidence: 99%

“…We utilized a recently characterized host model of zebrafish embryos that offers a number of advantages, including the ability to conduct higherthroughput analyses than conventional rodent models while involving an immune system that is more similar to mammals than other invertebrate models such as C. elegans. Moreover, P. aeruginosa infection in zebrafish embryos resembles rodent models of acute infection in that both quorum sensing and T3S are required for full virulence in zebrafish embryos (6,9).…”

mentioning

confidence: 99%

The Sensor Kinase KinB Regulates Virulence in Acute Pseudomonas aeruginosa Infection

et al. 2011

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Two-component sensors are widely used by bacteria to sense and respond to the environment. Pseudomonas aeruginosa has one of the largest sets of two-component sensors known in bacteria, which likely contributes to its unique ability to adapt to multiple environments, including the human host. Several of these two-component sensors, such as GacS and RetS, have been shown to play roles in virulence in rodent infection models. However, the role and function of the majority of these two-component sensors remain unknown. Danio rerio is a recently characterized model host for pathogenesis-related studies that is amenable to higher-throughput analysis than mammalian models. Using zebrafish embryos as a model host, we have systematically tested the role of 60 two-component sensors and identified 6 sensors that are required for P. aeruginosa virulence. We found that KinB is required for acute infection in zebrafish embryos and regulates a number of virulenceassociated phenotypes, including quorum sensing, biofilm formation, and motility. Its regulation of these phenotypes is independent of its kinase activity and its known response regulator AlgB, suggesting that it does not fit the canonical two-component sensor-response regulator model.

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“…1F). The morphological changes might be associated with alterations in cell motility or the infection of the leukocytes themselves (30,31).…”

Section: Resultsmentioning

confidence: 99%

Cellular Visualization of Macrophage Pyroptosis and Interleukin-1β Release in a Viral Hemorrhagic Infection in Zebrafish Larvae

Varela

Romero

Dios

et al. 2014

J Virol

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Hemorrhagic viral diseases are distributed worldwide with important pathogens, such as dengue virus or hantaviruses. The lack of adequate in vivo infection models has limited the research on viral pathogenesis and the current understanding of the underlying infection mechanisms. Although hemorrhages have been associated with the infection of endothelial cells, other cellular types could be the main targets for hemorrhagic viruses. Our objective was to take advantage of the use of zebrafish larvae in the study of viral hemorrhagic diseases, focusing on the interaction between viruses and host cells. Cellular processes, such as transendothelial migration of leukocytes, virus-induced pyroptosis of macrophages. and interleukin-1␤ (Il-1␤) release, could be observed in individual cells, providing a deeper knowledge of the immune mechanisms implicated in the disease. Furthermore, the application of these techniques to other pathogens will improve the current knowledge of host-pathogen interactions and increase the potential for the discovery of new therapeutic targets. IMPORTANCEPathogenic mechanisms of hemorrhagic viruses are diverse, and most of the research regarding interactions between viruses and host cells has been performed in cell lines that might not be major targets during natural infections. Thus, viral pathogenesis research has been limited because of the lack of adequate in vivo infection models. The understanding of the relative pathogenic roles of the viral agent and the host response to the infection is crucial. This will be facilitated by the establishment of in vivo infection models using organisms such as zebrafish, which allows the study of the diseases in the context of a complete individual. The use of this animal model with other pathogens could improve the current knowledge on host-pathogen interactions and increase the potential for the discovery of new therapeutic targets against diverse viral diseases.

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Pseudomonas aeruginosaType III secretion system interacts with phagocytes to modulate systemic infection of zebrafish embryos

Cited by 121 publications

References 62 publications

Characterization of the mononuclear phagocyte system in zebrafish

Characterization of the mononuclear phagocyte system in zebrafish

The Sensor Kinase KinB Regulates Virulence in Acute Pseudomonas aeruginosa Infection

Cellular Visualization of Macrophage Pyroptosis and Interleukin-1β Release in a Viral Hemorrhagic Infection in Zebrafish Larvae

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