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Doctoral school affiliation and University: Complexité du Vivant (ED515) – Université Pierre et Marie Curie
Presentation of the laboratory and its research topics:
We study the progressive emergence and functional traits of the innate immune system in vertebrate development, using the assets of a small tropical freshwater fish, the zebrafish, to address questions that are difficult to approach in mammals. The full transparency of zebrafish embryos and swimming larvae notably allows us to image cell behaviours in vivo at high resolution, in a totally non invasive manner. We study the successive developmental waves of hematopoiesis that ultimately give rise to the deployment of resident leukocytes in the tissues. Then among these leukocytes, we investigate the respective roles, behaviour, and mechanisms of chemoattraction of the professional phagocytes, macrophages and neutrophils, both in the uninfected organism and upon encounter of commensal or potentially pathogenic microbes. Finally we study the host response to viral infections in real time, to learn how a viral infection propagates in the organism, and which cellular and molecular defences the latter mobilizes to contain or eradicate the virus.
Description of the project:
The immune system starts developing very early during development, and from a very early stage, zebrafish embryos possess functional innate immune cells that allow them to ward off infections. Several waves of hematopoiesis give rise to these cells, whose multiple lineages are only partially understood; their functions appear more diverse than originally expected. The aim of this PhD proposal would be to unravel the origin of the diversity of some of these cell types by a combination of in vivo imaging and single cell transcriptome analysis.
More specifically, this project will address the lineages of cells with specialized antiviral function. Recently, thanks to a transgenic reporter line developed in our laboratory, we have identified a subset of interferon-producing cells in zebrafish larvae (1). Surprisingly, most of these cells turned out to be neutrophils. Do interferon-expressing neutrophils constitute a distinct lineage from other neutrophils? To answer this question, the origin, progeny, and expression profiles of transgene-positive and -negative neutrophils, will be studied in both naïve and infected animals. Another, macrophage-like, population of leukocytes has also been observed to express the transgene, and will also be characterized. Pathways of virus sensing will be analysed in depth in these different cell subsets. These studies should shed light on the evolutionary origin and ontogeny of specialized IFN-producing cells of mammals such as plasmacytoid dendritic cells.
To perform these studies, the PhD student will rely on live imaging of hematopoietic cells, combining confocal and Normarski optics, a specific technical strength of the laboratory (2). Other important methods already mastered in the lab will include microinjection of pathogens, genetic manipulation of larvae, mostly by injection of antisense morpholinos, and flow cytometry-activated sorting of small cell populations. In addition, he/she will have to develop a single-cell multiplex qPCR system for zebrafish cells, by adapting tools already available for other species in the Department.
(1) Palha N., Guivel-Benhassine F., Briolat V., Lutfalla G., Sourisseau M., Ellett F., Wang C.-H., Lieschke G.J., Herbomel P., Schwartz O. & J.-P. Levraud. « Real-time whole-body visualization of Chikungunya virus infection and host interferon response in zebrafish». PLoS Pathogens, in press.
(2) Renaud O., Herbomel P. & K. Kissa. Studying cell behavior in whole zebrafish embryos by confocal live imaging: application to hematopoietic stem cells. Nature Protocols 6 :1897 (2011)
There is no absolute requirement for a candidate except curiosity. Having studied developmental biology and/or immunology would be an advantage. Previous experience with zebrafish handling, confocal microscopy, FACS and/or molecular biology (notably qPCR) would also be welcome.