Early responses to Parasites and Immunopathology  


  HEADLOUIS Jacques A. Professor / jlouis@pasteur.fr
  MEMBERSResearchers: Dr BUZONI-GATEL Dominique, Dr DOYEN Noëlle, Dr MECHERI Salah, Dr WERTS-LARZILLIÈRE Catherine
Tempory scientists: PORCHERIE Adeline (post-doc), SCHNEIDER Bradley(post-doc) HKIMA ABOU FAKHER Faihaa, SCHULTHESS Julie. BEGHDADI Walid, Mc COY Margaret, CHEVALIER Grégoire (Master 2), FERHANI Nassima (Master 2), GUAY Jean-Christophe (Master 2)
Research engineer: DARCHE Sylvie
Technicians: KLIMCZAK Martine, PERONET Roger
Secretary: MEIGNAN Marie-Laurence


  Annual Report

The study of the mechanisms underlying genetic differences in the development of pathogenic Th cells following infection with intracellular parasites is a major theme of the Unit. One group investigates some early events shaping the protective Th1 response developing in C57BL/6 mice following infection with Leishmania major. The role of cells from the innate immune system for initiating this protective adaptive T cell response is particularly studied. An other 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 induced by oral administration of Toxoplasma gondii in C57BL/6. The last group studies the cellular and molecular changes in the skin and lymph nodes and other organs of mice induced by the bites of Anopheles mosquito infected with Plasmodium and their effects on the immune response against Malaria parasites.

Using genetically resistant C57BL/6 mice deficient in either TLR2, 4 or 9 we showed that only TLR9-deficient mice are more susceptible to infection with L. major. The absence of TLR9 also transiently inhibited the development of curative Th1 response. Studies aiming at assessing possible basis for such aberrant response in TLR9-deficient mice have shown that TLR9 expression is required for the activation, by either heath-killed or live L. major, of dendritic cells derived either in vitro from bone marrow progenitors or freshly isolated from the spleen of C57BL/6 mice. Results from two separate approaches pinpointed the DNA of L. major as the possible ligand of TLR9 leading to the activation of dendritic cells.

We showed that the T. gondii-induced Th1 inflammatory responses in the intestine require signaling through TLR9, in the hematopoietic and non-hematopoietic compartments. TLR9 expressing B cells participate to the initiation of this overwhelming intestinal Th1 immune response through membrane bound TNF-αand direct interaction with CD4 T cells from the lamina propria. Intra-epithelial lymphocytes down-regulate the magnitude of the Th1 response through TGF-βeither 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.

A hallmark of the host response to inoculation of Plasmodium via Anopheles mosquito bites or via later stages of the parasite is an inflammatory reaction characterized by high histamine levels. We have used genetic and pharmacological approaches to assess the role of histamine in malaria pathogenesis. Results demonstrate the importance of histamine in the pathogenesis of infection with Plasmodium since inhibition of histamine-mediated signaling conferred significant protection against severe malaria in murine models of diseases. Understanding the basis for these remarkable effects of histamine may lead to novel therapeutic strategies to alleviate the severity of malaria.

Keywords: Tcell subset differentiation, Tcell and pathogenesis of infection with parasites, Innate immunity to parasites, Toxoplasma Gondii, Leishmania major, Malaria pathogenesis



  Publications

Demeure CE, Brahimi K, Hacini F, Marchand F, Peronet R, Huerre M, St-Mezard P, Nicolas JF, Brey P, Delespesse G, Mecheri S. Anopheles mosquito bites activate cutaneous mast cells leading to a local inflammatory response and lymph node hyperplasia. J Immunol.2005, 174(7):3932-40.

Depinay N, Hacini F, Beghdadi W, Peronet R, Mécheri S. Mast Cell-Dependent Down-Regulation of Antigen-Specific Immune Responses by Mosquito Bites. J Immunol. 2006, 176: 4141-4146.

Gumy. A.,Aseffa,. A., Rachinel, N., Breton. M., Otten. L., Tacchini-Cottier. F., Röcken. M., Doyen.N., Acha-Orbea. H., Locksley. R. M., MacDonald. H. R., Launois. P., Louis.J. LACK reactive CD4+ T cells require autocrine IL-2 to mediate susceptibility to Leishmania major. Eur.J. Immunol. 2006; 36, 1465-1473

Menard L, Minns L, Darche S, Mielcarz, Fourreau D, Roos D, Dzierszinski F, KasperL, Buzoni-Gatel D. B cells amplify IFN-γProduction by T cells via a TNF-α mediated mechanism. J. Immunol.2007 179 : 4857-4866

Buzoni-Gatel D, Werts C. Toxoplasma gondii and subversion of the immune system, Trends Parasitol. 2007. Oct; 22(10):448-52. Review





Activity Reports 2007 - Institut Pasteur
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