The SRC Kinase Adaptor Phosphoprotein 2 (SKAP2), a broadly expressed protein with some higher expression in haematological lineages recruiting protein partners to specific subcellular domains, plays a central role in multiple physiological processes in relation with cell migration. We have linked this gene in interaction with CNTNAP5 to susceptibility to Dengue Shock Syndrome in a cohort of Vietnamese patients. By coupling a yeast-two-hybrid screen with a luciferase complementation assay and mutagenesis, we would like to understand how are the different functions of SKAP2 modulated by protein-protein interactions (PPI). We will also study SKAP1 paralog, which has similar but non-redundant functions, to compare their PPIs. The hub will have to analyze these multidimensional data to statistically validate which function is affected by each PPI and SKAP2 mutation and define common patterns. One goal of these analyses will be to define new hypotheses in particular for characterizing binding sites that will be secondary tested.

Adaptive immune cells play important role in pathogenesis of multiple sclerosis by infiltrating the central nervous system, thereby contributing to demyelination and maintenance of an inflammatory microenvironment. In particular, autoreactive T cells, CD4+ T helper and CD8+ T cells exert a detrimental effect, while CD4+ regulatory T cells (Treg) have impaired suppressive function. Interferon b (IFNb), a commonly prescribed treatment for relapsing-remitting multiple sclerosis (RR-MS) decreases relapse rates and brain disability progression. However, around 30% of patients are or become non-responsive to treatment. Our aim is to determine the immune signatures associated with clinical efficacy of IFNb treatment in RRMS patients

Urinary Tract Infections (UTIs) represent approximatively 150 to 250 million cases per year, thus are of major public health concern. 80% of community-acquired UTIs are caused by UPECs and about 40% of UPECs are known to produce the Cytotoxic Necrotizing Factors1 (CNF1). The CNF1 is a Rho-activating toxin that catalyzes a specific deamidation of a glutamine of Rho GTPases for cells invasion. The deamidation maintains the GTPases constitutively activated and the constant activation of RhoGTPases by CNF1 leads to proteasomal degradation through K48 ubiquitination. However, the change in proteins expression levels, the rate of modification induced by the CNF1 on the cellular proteome and the outcomes of host responses have not yet been investigated. By conducting quantitative mass spectrometry–based proteomics approaches, we intend to describe changes of the cellular proteome during cell invasion by UPEC producing CNF1.

The transcriptome signature during rabies infection will be analyzed both in animal model (mouse) and in human, at the central nervous system level, to identify the main canonical pathways involved during the infection.

Energy demands vary widely depending on cellular activation states. Here we perform an integrated bioenergetic analysis (epigenetic, transcriptomic and metabolomic) of the human CD56Br and CD56Dim natural killer (NK) cell subsets under steady-state conditions and after cytokine activation. We found that CD56Dim NK cells were metabolically active at steady state, but that both subsets increased bioenergetic properties upon priming with IL-15, with metabolic profiles similar to tonsillar NK cells. In contrast, IL-12/IL-18-induced cell activation promoted a dichotomous response with an elevated respiratory and functional capacity in CD56Br NK cells versus a metabolic switch towards glycolysis and reduced IFN-γ production in CD56Dim NK cells. The latter was associated with mitochondria fragmentation; inhibition of which increased IFN-γ production. Polarized mitochondria were identified with the CD57+ CD56Dim NK cell subset, thereby identifying a potential signature for NK cell functional maturation. We propose mitochondrial remodeling as a key regulator of NK cell function.

Left-right asymmetry of the heart is essential for establishing the double blood circulation. Impairment of left-right embryo patterning is associated with severe congenital heart defects. During embryonic development, the heart initially forms as a straight tube. While it elongates, it acquires the shape of a rightward helix, a process referred to as heart looping. Previous work suggests that dynamic signaling in the heart precursor cells are essential for heart looping completion, but so far only a few genes have been identified as asymmetrically expressed. In order to investigate the dynamic spatiotemporal patterning of heart precursors, and screen for novel players in asymmetric heart morphogenesis, we aim to perform several transcriptomic analyses.

We propose to identify peptides derived from the S protein that can modulate the HLA-E restricted activity of NK cells. Through in-silico analyses, we have already identified in the S protein of SARS-Cov1, SARS-Cov2 and MERS-Cov regions coding for peptides with HLA-E binding motifs. We will perform functional and structural analyses of the binding of these peptides to MHC-E. We will study MHC-E restricted responses of NK cells in blood and tissues during SARS-Cov2 infection in non human primates. From longitudinally collected samples from blood and tissues before and after the SARS-CoV2 infection of the animals, we will analyse the phenotype and transcriptome profile of NK cells and compare to viral loads and disease progression of the animals.

This project aims at characterizing the transcriptional signature of skeletal muscle during regeneration.

Establishment of a left-right asymmetry is essential for the function of the heart, which is to ensure a double blood circulation. This asymmetry is initiated during an embryonic process, in which the heart tube acquires a loop shape. The molecular cascade at the origin of left-right asymmetry is well established and involved in the severe heart defects of the heterotaxy syndrome. However, another 20% of heart malformations display cardiac chamber misalignment and their origin is poorly understood. Using a mutant mouse model and expertise in heart morphogenesis, we want to provide novel insight into malformations displaying an abnormal alignment of ventricles.

Bacterial toxins can induce a wide range of life threatening diseases and are at risk of bioweapon development due to their extreme toxicity and ease of production. Some AB-like toxins exploit the host cell endocytic machinery to enter into the cell cytosol where they exert their poisoning effects. Host-targeted therapy involving the development of small molecules interfering with key vesicular trafficking components hijacked by bacterial toxins offers to counteract toxin action. We have identified the small compound C910, in a cell-based High-throughput screen (HTS) followed by orthogonal screens described in (Mahtal N et al., 2018), for its cell-protective activity against CNF1 toxin from pathogenic Escherichia coli, as well as diphtheria and Shiga toxins. Therefore, to characterize C910 mechanism of action and find its cellular target we have realized an siRNA wide-genome screening on primary human cells. This screening aims to find genes that can interfere with the trafficking of the CNF1 toxin.

Proteomes of different cellular compartments of choanoflagellates will be compared to omic datasets from other species to gain insights into the evolution of animal cellular phenotypes.

Leptospirosis is a re-emerging zoonosis that affects more than one million people and causes nearly 60,000 deaths per year worldwide. This disease transmitted to humans via an environment contaminated by bacteria of the genus Leptospira has a record incidence in Oceania. Pathogenic leptospires are able to survive for several weeks in the environment. The production of a biofilm allows them to efficiently resist to hostile conditions and would explain their persistence in the environment. Our recent work has shown that the regulation of biofilm formation is under the control of cyclic di-GMP, an intracellular second messenger recognized as a signaling molecule coordinating the transition between motile (planktonic) and sessile (biofilm) life styles. This project aims to determine the role of cyclic di-GMP in the regulation of pathogenesis and biofilm formation in Leptospira interrogans in order to better understand the environmental survival of this pathogenic bacterium.

We are interested in the behaviour of healthy cells in the context of tumour growth in the Drosophila brain We want to know the genes changing in healthy cells response to the tumour.

African trypanosomes are flagellated protist parasites transmitted to mammals by the infectious bite of the tsetse fly. They are responsible for sleeping sickness in humans and nagana in cattle. Trypanosomes first proliferate freely in the blood, and then, about six hours after being inoculated, leave the bloodstream to invade various organs, including the skin, which is an anatomic reservoir for the parasites. Few details are known on the metabolic aspects of the different parasite stages in the blood and in the skin, as well as the immune response of the mammalian host against the different stages of development of dermal parasites. Two strains of trypanosomes (“AnTat1.1E” and “Lister 427”) with different genetic profiles were studied here: one having only one developmental stage named "SL" or slender in reference to their tapered shape in mice, the second having two developmental stages "SL", and "ST" for stumpy in reference to their stocky shape in mice. This will allow us to distinguish the transcriptomic signature of parasites at the ST stage. Mice were sampled 5 days or 4 weeks after experimental infection in order to evaluate how the parasite transcriptome evolves over the course of an infection. In all these conditions, blood and skin samples were taken in order to compare the transcriptomes of blood and dermal parasites on the one hand, and transcriptomes of murine blood and dermal tissues on the other. We will especially scrutinize the metabolic pathways of the two parasite strains in the blood and the skin, as well as the immune response of the host in each compartment, two crucial elements determining the development of the infection.