Early responses to Parasites and Immunopathology - INRA USC2010  

  HEADProf. LOUIS Jacques A. / jlouis@pasteur.fr
Dr DOYEN Noëlle / FERHANI Nassima / GUAY Jean-Christophe

  Annual Report

We study mechanisms underlying genetic differences in maturation of pathogenic Th cells following infection with intracellular parasites. One group analyses the cellular and molecular mechanisms accounting for the induction and regulation of a pathogenic T cell response in a model of inflammatory bowel disease. In this model a cell-mediated intestinal inflammation is induced in C57BL/6 mice following oral administration of Toxoplasma gondii. We also investigate some early events shaping the induction of the Th2 response resulting in progressive disease in BALB/c mice infected with Leishmania major and the protective Th1 response in C57BL/6 mice. The nature of the T cell-intrinsic factors in Th2 cell maturation are analysed in susceptible mice. The importance of cells of the innate immune response for initiating the Th1 protective adaptive response is studied in resistant mice. One group studies the cellular and molecular changes in the skin and lymph nodes of mice induced by the bites of Anopheles mosquito and their effects on the immune response against Malaria parasites.

We showed that the T. gondii-induced Th1 inflammatory responses in the intestine require signaling through TLR9, in the hematopoietic and non-hematopoietic compartments. Intra-epithelial lymphocytes down-regulate the magnitude of the Th1 response through TGF-β either secreted or membrane bound. The activation of NKT cells also seen in this system appears facilitated by IL-15. Recent results have shown that IL-15 produced by enterocytes infected with T. gondii initiates the ileitis-inducing inflammatory immune response. Importantly the cells transporting T. gondii to the brain after oral infection were characterized.

The burst of IL-4 transcripts in response to Leishmania major in susceptible BALB/c mice that occurs in CD4+ cells specific for an epitope of this parasite requires autocrine IL-2. This burst of IL-4 instructs the Th2 cell maturation in susceptible mice. The inability of resistant mice to express an early IL-4 response to L. major might stems from the incapacity of these cells to produce IL-2. Concerning the role of innate responses in carving adaptive protective responses in resistant mice, we observed that TLR9 deficient mice on a resistant background were initially significantly more susceptible to L. major. Although L. major failed to activate conventional Dendritic cells (DC), it led to robust activation of plasmacytoid DC (pDC) provided the TLR9 signaling pathway was functional. Parasite DNA is a constituent able to activate pDC.

The saliva of Anopheles mosquito activates mast cells, leads to an inflammatory response and draining lymph nodes hyperplasia. Since mast cells activation results in the release of histamine, the role of this vaso-active amine on infection with Plasmodium berghei was studied. Using several approaches, a strong link between the severity of Malaria and histamine in this murine model of infection was discovered. The cellular and molecular bases for such an effect of histamine are currently being studied.


Publications 2006 of the unit on Pasteur's references database

Activity Reports 2006 - Institut Pasteur
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