Macrophages and Development of Immunity - CNRS URA2578  


  HEADDr HERBOMEL Philippe / herbomel@pasteur.fr
  MEMBERSDr COLUCCI-GUYON Emma / Dr KISSA-MARIN Karima / LE GUYADER Dorothée
Dr LEVRAUD Jean-Pierre / Dr MURAYAMA Emi / TAUZIN Muriel


  Annual Report

We focus on the emergence and functional traits of the first innate immune cell types in vertebrate development, using zebrafish embryos. This led us to investigate also the transition from primitive to definitive hematopoiesis. Finally we use the zebrafish model to study innate responses to infections in the live animal at high resolution.

Macrophages, granulocytes, and developmental hematopoiesis

In all vertebrate embryos, the first leukocytes to arise are the primitive macrophages, which we showed to originate from a distinct mesoderm adjacent to the cardiac field. These cells differentiate in the yolk sac, then quickly invade the still unvascularized embryonic tissues, notably the brain and retina where they become primitive microglia. Recently we explored the basis for their naturally invasive behaviour and found that their colonization of the brain and retina required their expression of a specific matrix metalloprotease

Neutrophilic granulocytes appear a day later, throughout the embryo, surprisingly barely in the blood, but mostly wandering in the mesenchyme and epidermis. Using in vivo photoactivatable cell tracers, we found them to arise from two origins: i) the progenitors of the primitive macrophages, which we thus discover to be bipotent; ii) a previously undescribed caudal hematopoietic tissue, which we found to be a transitional site for the homing, expansion and differentiation of definitive hematopoietic stem cells, before their migration to the final hematopoietic organs.

Within the european Integrated Project "ZF-Models", we performed two screens for mutants defective in macrophage or granulocyte differentiation or tissue invasion. We found many, and are now analyzing further the phenotypes of the most promising ones.

Innate host responses to infections

Mycobacterium marinum, the agent of fish tuberculosis, is very close to its human counterpart. The complex glycolipids of the cell wall of mycobacteria are thought to be a major factor of their pathogenicity. We inject these components purified from M. marinum in zebrafish larvae, either as such or coupled to fluorescent beads, and assess their effects on phagocytosis, cell recruitment, granuloma formation, or induction of host genes.

We also set up an experimental system of viral infection of zebrafish embryos, which makes it possible to exploit antisense technology to assess the anti-viral effects of any virus-induced host gene. This already allowed us to identify functionally the two chains of the fish interferon (IFN) receptor among all class II helical cytokine receptor genes, which led us to conclude that the ancestral innate IFN system is neither IFN-α nor -ß, but IFN lambda.

herbomel.jpg

Une larve type sauvage (WT) a des granulocytes (points noirs) dispersés dans ses tissus, tandis que le mutant NL144-01 (homozygote viable) n'en a aucun.

Figure: A wild-type fish larva has granulocytes (black dots) dispersed in the tissues; an NL144-01 (homozygous viable) mutant larva has none.



  Publications

Publications 2006 of the unit on Pasteur's references database




Activity Reports 2006 - Institut Pasteur
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