Characterization of the relationship between Brucella melitensis and the innate immune system of the mouse

Résumé

Brucella melitensis is a facultative intracellular pathogen responsible for brucellosis, one of the world’s most widespread zoonotic diseases causing abortion in domestic animals and a chronic granulomatous infection in humans. A key pathogenic trait of this organism is its ability to survive in immune cells such as macrophages and persist in tissues of the reticuloendothelial system, including the spleen and liver. The crucial component of immunity that results in survival of the host and thus maintenance of the chronic infective state is interferon-γ (IFN-γ), the cardinal mediator of the T helper 1 (TH1) immune response. Production of IFN-γ results from the ability of Toll-like receptors to detect Brucella components and induce production of Interleukin- 12 (IL-12). One of the major roles of IFN-γ is the stimulation of Brucella-killing processes, such as the production of reactive nitrogen intermediates by inducible Nitric Oxide Synthase (iNOS/NOS2) in phagocytic cells. Despite progresses in experimental animal models of brucellosis, much remains unknown regarding the characterization of the effector mechanisms induced by B. melitensis infection. In particular, the nature and cell surface phenotype of innate immune effectors implicated in Brucella control are largely undetermined. By using a combined histologic and flow-cytometric approach, we thus decided to study the relationship between B. melitensis and the immune system of the mouse by focusing on the description of the nature and function of the immune effector mechanisms developed by the host. In the current study, we report the identification of the iNOS-producing dendritic cells (inflammatory DC) as the main iNOS-producing cells recruited and activated in the spleen and peritoneal cavity of the mouse during the early stages of B. melitensis infection. We identify the crucial role of TLR4/9 and MyD88 dependent signaling cascade in the activation of these cells. By using immunohistofluorescence techniques, we demonstrate the importance of inflammatory DC in the development of granulomas structures in the spleen and liver of infected mice and we delineate the negative impact of MyD88 deficiency on the establishment of these structures. Additionally, we describe the phenotype of B. melitensis infected cells in spleen and liver during the five first days of infection. Finally, we show that B. melitensis induces the migration and maturation of DCs in the spleen, in a dose dependant manner. In conclusion, this work dissects for the first time the nature of the effectors mechanisms developed by the immun

la date de réponse	28 sept. 2010
langue originale	Français
L'institution diplômante	Universite de Namur
Superviseur	JEAN-JACQUES LETESSON (Promoteur), Ignacio Moriyón (Jury), Stefan Magez (Jury), Camille LOCHT (Jury) & Éric Muraille (Copromoteur)