Unit: Early responses to parasites and Immunopathology

Director: Jacques A. LOUIS

An important goal of this new unit is to study, in vivo, the mechanisms leading to different T cell responses in genetically distinct hosts following infection with intracellular parasites such as Leishmania and Toxoplasma. One group focuses on the early events shaping the Th2 response resulting in susceptibility to Leishmania major in BALB/c mice. Another group studies the Th1 response leading to an inflammatory bowel disease in mice from some strains following oral infection with Toxoplasma gondii. The mechanisms by which cutaneous mast cells modulate, upon activation by Anopheles salivary components, the innate and specific immune responses during malaria infection are also studied.

The research of the group of J. Louis will continue to focus on the study of the mechanisms underlying genetic differences in CD4+ Th subset maturation using the murine model of infection with L. major. In summary, previous work from the group has revealed, following infection of susceptible BALB/c mice, an early burst of IL-4 transcription among CD4+ T cell expressing the Vb4-Va8 TCR chains and reactive to the Leishmania homolog of mammalian RACK1 (LACK). This IL-4 response plays a role in driving aberrant Th2 cell development and disease progression in these mice. Although this early IL-4 response was not seen in resistant C57BL/6 mice, neutralization of either IL-12 or IFN-g at the initiation of infection allowed the expression of an early IL-4 response in these resistant mice. Thus, an impairment of mechanisms able to down-regulate rapid IL-4 production by Vb4-Va8 CD4+ T cells might, at least in part, underlie the susceptibility of BALB/c mice to L. major. Recent studies by others, using multivalent MCH/peptides and IL-4 reporter mice, although confirming the pathogenic role of these LACK-specific CD4+ T cells in the expression of a susceptible phenotype, have however shown that the precursor frequency, expansion and IL-4 production of these cells were identical in susceptible BALB/c and resistant B10D2 mice. These and other results suggest that signals other than IL-4 are also involved in Th2 cell development and susceptibility to infection with L. major. Thus, in the coming years, although an aspect of our project will concern the study of the regulation of IL-4 production by these Vb4-Va8 CD4+ T cells, other aspects will be investigated such as : -analysis of possible differences in responsiveness to IFN-g between resistant and susceptible mice ;-study of the possibility that L. major is recognized by Toll-Like Receptors (TLRs) on Dendritic Cells (DCs) and that TLRs signaling participate to the shaping of the protective Th response in resistant mice.

The group of D. Buzoni-Gatel will continue to focus on the murine model of inflammation in the small intestine that is induced following oral infection with T. gondii. This model is unique, not only for the investigation of the cellular and molecular basis of this pathogen-driven inflammation, but also for a better understanding of the various parameters of the host mucosal response to this and perhaps other opportunistic pathogens. During the initial stage of infection, we will evaluate the process by which this parasite induces the lethal inflammatory ileitis. An important aspect of our project is concerned with the study of the role of the gut-derived dendritic cells in processing and presenting the major surface antigen SAG1 (P30) of Toxoplasma gondii that can elicit this hyper-inflammatory immune response. The possibility that interactions between the intestinal microflora and the obligate intracellular protozoan pathogen, T. gondii, contribute to regulation of the gut immune homeostasis will also be assessed. In addition, we will also study the pathogenesis of the Toxoplasmic encephalitis. In this context, the role of dendritic cells, naturally infected with T. gondii in the establishment of chronic cerebral infection by T. gondii will be evaluated.

The group of S. Mecheri will continue to study the effects of components of the Anopheles' saliva on the innate and adaptative immunity during malaria infection. The skin is one of the preferred sites of entry for various pathogens. Among resident immune cells in this tissue, mast cells are found in relatively large numbers adjacent to blood and lymphatic vessels. Mast cells are highly reactive cells specialized for the synthesis and secretion of a myriad of pharmacologically active products. In the dermis, mast cells were found to be intimately connected to dendritic cells and together represent a first line of defence against pathogens. Mosquito bites are known to induce immediate as well as delayed hypersensitivity reactions. Our hypothesis is that salivary components, which contain pharmacologically active compounds as well as IgE-inducing allergens, may account for cutaneous mast cell activation and immune deviation in favour of the parasite. Since mast cells co-localize with immature dendritic cells in the skin and may be rapidly and directly activated by pathogens or antigens, we postulate that the mast cell-dependent inflammatory reactions induced by mosquito saliva shape both the function of dendritic cells and the nature of the subsequent T cell response. Using in vitro as well as the well-established in vivo model of mast cell deficient W/Wv mice we will explore whether mast cell activation induced by mosquito saliva modulates innate and specific immune responses against malaria sporozoites and whether this activation has an effect on the outcome of the disease. Specifically, we will explore whether 1) components of mosquito salivary gland directly induce mast cell degranulation, 2) saliva-induced mast cell activation modulate dendritic cell maturation and function, 3) saliva-induced mast cell activation deviates the immune response to Plasmodium in favor of the parasite. This project may lead to new vaccine strategies against malaria by primarily manipulating the immunomodulatory properties of vector's saliva.

Keywords: Leishmaniosis , Toxoplasmosis , Malaria , Immunopathology , Parasitology

Activity Reports 2003 - Institut Pasteur

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