Immunophysiology and Intracellular Parasitism

  HEADDr MILON Geneviève /

  Annual Report

In the entity “Immunophysiology and Intracellular Parasitism”, there is a continuous focus on the Leishmania life traits per se. We do extend our understanding of the stepwise processes that assess the long term interactions Leishmania establish and renew with

i) the mammal phagocytic leukocytes left unexposed to any exogenous signal

ii) the phagocytic leukocytes exposed to a balanced combination of pro- and counter-inflammatory signals i.e. with cells hosting persisting Leishmania amastigotes. High throughput screening readout assays have been selected to assist in designing novel interventions aimed to target both the cell-cycling and the persisting amastigote populations. This integrative approach - initiated since years - is expected to provide novel data on the dynamic features of both

  1. the amastigotes and

  2. the host niche(s) where they either cycle or persist.

Designing reliable mouse models for deciphering the stepwise developmental programs of Leishmania in the host cell lineages and/or host tissues they rely on for their perpetuation. Though we are aware that each phase, in the Leishmania-loaded dermis, assesses the otherwise versatile activities of many different leukocyte lineages [neutrophils, macrophages, macrophage related dendritic cells/DCs and effector and regulatory T lymphocytes] we decided to first focus on the phagocytes the amastigotes subvert as bona fide host cells. Affymetrix GeneChip oligonucleotide array technology was applied to total RNA carefully extracted from either L. amazonensis–loaded (a) bone marrow derived macrophages (b) DCs. Many robust signatures of the silent entry/establishment of the Leishmania amastigotes have been documented for both the macrophages and the DCs and different software applications are under screening for extracting other biologically relevant transcriptional signatures of L. amazonensis–loaded phagocytic leukocytes.

Bringing data from mouse models closer to the clinical reality: designing and standardizing a reliable mouse model of localized human cutaneous leishmaniasis/LCL.

Previously we designed and refined a mouse-based model with the objectives to analyze many parameters simultaneously, among which the ones that may influence the efficiency of any topical formulation expected to replace the limited number of drugs that are far from being optimal for humans displaying LCL. Mice (C57BL/6) that have received intradermally 104 transgenic bioluminescent L. major displayed the unique features of the human LCL i.e. the development of localized dermal lesions followed by spontaneous healing over weeks to months. The use of a transgenic bioluminescent L. major is a key advantage allowing two simultaneous readout assays to be standardized i) the parasite load fluctuations and ii) the clinical features, so that the relationship between parasite population size fluctuations and parasite-loaded skin features could be evaluated in real time. Thus, as a surrogate for the clinical efficacy testing, this model could offer preclinical relevant readout assays

  1. of the efficacy of an ointment topically applied or not under occlusion

  2. for establishing the proper regimen schedule according to the features of the damaged skin/lesion, the objectives being to allow standardized comparison of different approaches for human LCL therapy or prevention.


Publications 2006 of the unit on Pasteur's references database

Activity Reports 2006 - Institut Pasteur
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