Projects

The absence of classical transcriptional regulation through cis-acting sequence elements and transacting factors in Leishmania and the largely constitutive expression at both transcript and protein levels raise the question on how these parasites regulate the developmental transition between insect-stage promastigotes and vertebrate-stage amastigotes, and how they can evolve intra-species divergence in drug susceptibility, tropism, and infectivity as documented in numerous epidemiological field studies.

 

We scientifically address these questions by (i) investigating parasite-specific molecular mechanisms that govern Leishmania environmental adaptation using systems-wide analyses, and (ii) applying functional genetic approaches on underlying molecular players to reveal their biological relevance in parasite viability and infectivity.

 

We then translate our basic research findings on Leishmania-specific biology into preclinical applications through drug target validation and anti-leishmanial compound screens. Today, this scientific strategy to develop and apply innovative approaches to gain insight into parasite-specific biological processes relevant for therapy and disease prevention is at the core of two major research axes (Fig. 1).

 

The first axis is focused on the analysis of Leishmania signal transduction pathways that are relevant for adaptive parasite differentiation in the mammalian host and that qualify as novel targets for anti-parasitic drug development. We established and applied a series of genetics and phosphoproteomics approaches that provided important new insight into (i) the regulation of the Leishmania stress response at post-translational level, (ii) the role of chaperone expression and phosphorylation in parasite viability and infectivity, and (iii) the structure, function, and regulation of various Leishmania protein kinases.

 

The second axis investigates parasite-specific mechanisms of Leishmania genome plasticity and its consequences for parasite phenotypic variability.

 

Applying systems-wide approaches at protein, transcript, and gene levels allowed us (i) to link parasite environmental adaptation to genetic copy number variation implicating both amplifications and deletions at the chromosome and gene levels, and (ii) to reveal a mechanism of gene dosage compensation by epigenetic silencing through cis-regulatory long non-coding RNAs (lncRNAs). This peculiar Leishmania feature of genome plasticity bears direct relevance to the phenotypic variability observed in Leishmania field isolates with respect to drug susceptibility, pathogenicity, and tissue tropism, and will be at the core of a new translational effort in bio-marker discovery.

 

 

figure_1.jpg

 

Figure 1: The two major basic research axes of the ParSig Unit and their translational potential.

 

 

 

Updated on 25/07/2014

Contact

Gérald Spaeth - Head of Laboratory

Unit “Molecular Parasitology and Signaling”

Institut Pasteur

25-28 rue du docteur Roux

75015 PARIS

Phone:   +33.1.40.61.38.58

 

Sophie Veillault - Assistant

Phone:   +33.1.40.61.33.04

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