Development of monoclonal antibodies for the diagnostic and the treatement of hypervirulent-Klebsiella pneumoniae
For several years, we have observed the emergence of hypervirulent (hvKp) strains of Klebsiella pneumoniae that have become highly resistant to antibiotics. In a context of dwindling antibiotic options, monoclonal antibodies (Abs) directed against well-conserved capsular antigens of these hvKp strains appear as a promising therapeutic alternative.
This PhD project is structured around three complementary objectives:
1. To describe the circulation of hvKp clones through comparative genomic analysis of strains collected via the French National Reference Center for Antibiotic Resistance and through an international collaboration.
2. To produce and characterize monoclonal Abs directed against the HvKp capsule.
3. To develop a rapid detection tool based on MALDI-TOF profile analysis coupled with machine learning algorithms.
Acellular Biotherapy with Optimized Immunomodulatory Properties for the Prevention of Organ Injury in Traumatic Contexts
Severe trauma causes more than 5.8 million deaths worldwide each year, often associated with massive hemorrhages and multiple organ failure (approximately 33% of cases). Rhabdomyolysis, common in these patients, results from the destruction of muscle cells and leads to the release of their contents into the bloodstream. This complication promotes acute kidney injury and liver dysfunction. Currently, no specific treatment exists; management remains primarily symptomatic. Mesenchymal stromal cells (MSCs) are widely used for their immunomodulatory and regenerative properties. Preclinical studies have shown that IL-1ß-preconditioned MSCs can prevent kidney and liver damage and reduce vascular permeability after hemorrhagic shock. Their efficacy relies on the secretion of soluble factors and extracellular vesicles, known as acellular products. A large-scale, clinical-grade production method for these products, based on tangential flow filtration, has been developed. These products exhibit experimentally demonstrated immunomodulatory activity and hepatoprotective effects. Ready to use and easy to store, they represent a promising alternative to cell therapies in emergency settings. The objective of this thesis is to optimize the immunomodulatory and anti-inflammatory properties of these cell-free products by promoting their expression of two key immune tolerance molecules, PD-L1 and HLA-G. We will evaluate the interactions between these optimized products and various immune cells in vitro, and then in vivo in a traumatic hemorrhagic shock model (rat model).
Influence of Cytomegalovirus on Tissue-Specific Immune Responses in Non-Human Primate
Most studies in anti-infectious immunity focus on characterizing pathogen-specific immune responses and identifying strategies to optimize them. It is now essential to consider interindividual variability related to age, sex, metabolic status, and infectious history, which strongly influence these responses.
IDMIT’s expertise in preclinical modeling of viral infections provides an ideal framework to address these questions. Cytomegalovirus (CMV) infection represents a relevant model due to its high prevalence, its age-dependent effects, and its association with immune aging. Although epidemiological data suggest that CMV seroprevalence impacts responses to other infections and to vaccination, the underlying mechanisms remain poorly understood. We hypothesize heterogeneous effects related to the diversity of host–virus interactions across sites of viral persistence.
This project aims to characterize CMV-specific immune responses in blood and tissues of young and aged non-human primates, and in the context of chronic SIV infection. The objectives are (i) to assess age-related differences in viral dissemination and immune responses, (ii) to evaluate the predictive value of blood markers relative to tissue parameters, and (iii) to study the reciprocal modulation of CMV and SIV responses during co-infection.
These studies will contribute to the development of vaccination strategies targeting the deleterious effects of CMV and the tissue-specific modulation of immune responses.
Active matter: self-organization of mitotic spindles
The mitotic spindle is an essential cytoskeletal structure that enables chromosome separation during cell division. This project seeks to identify the physical principles that control spindle assembly by using a simplified biomimetic system composed solely of microtubules and molecular motors. We will use motors of opposite polarities combined with dynamic microtubules to understand how these components organize through active phase separation. Indeed, preliminary experiments have demonstrated that such reconstituted systems can spontaneously form bipolar structures resembling mitotic spindles. We now propose to encapsulate these molecular components in compartments of controlled geometry to reconstruct a minimal bipolar structure capable of elongating, retracting, and separating its organizing poles. This multidisciplinary approach will combine biochemical and physicochemical techniques, advanced microscopy, and quantitative analysis of the spatial and temporal evolution of the system. The experimental work will be closely coupled with theoretical modeling in collaboration with Prof. Jean-François Joanny (Collège de France) to develop a physical model of active phase separation that will provide better understanding of self-organization mechanisms at the subcellular scale in living organisms.
Origins and evolution of prion-like proteins (PrLPs) in eukaryotes
Initially associated with neurodegenerative diseases, prion-like proteins (PrLPs) are now recognized as key physiological players in cellular plasticity and stress response. These proteins often contain an intrinsically disordered domain rich in glutamine and asparagine, known as a prion-like domain (PrLD), capable of switching between soluble, condensed, or amyloid states. Notable examples include CPEB in Aplysia, involved in synaptic memory, MAVS in antiviral defense, MED15 and FUS in transcriptional regulation and nucleocytoplasmic condensate dynamics, and ELF3 in plants, whose amyloid polymerization controls flowering and photoperiodic responses. In fungi, Sup35, Ure2p, and HET-s serve as experimental models of functional prions, demonstrating that reversible aggregation can act as a regulatory or adaptive mechanism. These conformational transitions are now viewed as adaptive molecular strategies rather than pathological anomalies.
This PhD project aims to trace the origin and diversification of prion-like proteins across eukaryotes, testing the hypothesis that major paleoclimatic crises have episodically promoted the emergence and duplication of genes encoding PrLDs through microsatellite expansion and transposable element activity. The project will combine large-scale phylogenomic analyses, PrLD domain detection, and modeling of selective pressures to map the key stages in the functional evolution of PrLPs and their links to stress tolerance.
Explainable AI for interpretation of Small Angle Scattering
The PhD will be conducted in two laboratories at Paris-Saclay: one group with expertise in artificial intelligence developed over many years, MIA-PS (INRAE), and another in the physics of matter – soft matter, biology – MMB-LLB (CEA/CNRS).
Small-Angle Scattering techniques (X-rays, neutrons, light) involve a constantly growing community, particularly active in France, especially in soft matter and biology. The transition of data from reciprocal space to real space is achieved via different models – in which the MMB group is an expert – whether concerning shape – sphere, rod, platelet, polymer chain – or interactions – attraction, aggregation, repulsion, arrangement. Furthermore, more complex structures, such as proteins or irregular aggregates, require computational or empirical approaches. In all cases, the results are not unequivocal. This is particularly challenging for research groups new to the technique.
In this thesis, thanks to MIA-PS's expertise in AI (machine learning, optimization, visualization), the focus will be on developing explainable AI methods. Part of the modeling involves explained mathematical and physical models, while another part relies on so-called "black box" models, which will be progressively explained. The doctoral candidate will have access to data from three use cases provided by the LLB, and to their experts, to develop a generic methodology. A first step could be based on the globally shared software SasView, a treasure trove of explicit models. We have already received a positive response from the SasView developers, which could therefore serve as a dissemination tool. A valuable contribution will be the access to complementary DPA measurements via the LLB platforms and the SOLEIL and ESRF synchrotrons.
Subsequently, a component focusing on human-computer interaction—ensuring that users remain fully responsible for constructing a physico-chemical-biological explanation—can be implemented. MIA-PS is also an expert in advanced interactive visualization methods.
This project therefore combines highly advanced developments in computer science with a wealth of real-world systems chosen for their originality and, of course, their potential applications.
Endothelial-fibroblast interactions in diabetic foot ulcer: deciphering the intercellular communication responsible for the chronic wound persistence
Diabetic foot ulcer (DFU), a severe complication of diabetes affecting approximately 18.6 million people worldwide each year, is associated with high rates of amputation and mortality. Like other chronic wounds, DFUs exhibit impaired healing due to a dysregulated cascade of cellular signalling and behavioural events that normally ensure rapid closure of the skin barrier. Among the key cellular players, fibroblasts and endothelial cells are central to the proliferative and remodelling phases of wound repair – processes that are notably dysfunctional in chronic wounds. Although endothelial-fibroblast crosstalk is recognized as an essential driver of normal skin healing, the specific mechanisms governing their interaction in DFU is poorly understood.
The main objective of this PhD project is to decipher the intercellular communication between endothelial cells and fibroblasts that underlies the chronicity of DFU. Particular attention will be devoted to extracellular vesicle-associated microRNAs (miRNAs), which are pivotal regulators of intercellular communication through modulation of gene expression in recipient cells. By characterizing the repertoire of pro- and anti-healing miRNAs exchanged between endothelial cells and fibroblasts, this project seeks to uncover novel molecular targets and therapeutic strategies to promote wound repair in diabetic foot ulcers.
V-SYNTHES-guided discovery of BET bromodomain inhibitors : a novel antifungal strategy against Candida auris
New antifungal strategies are urgently needed to combat Candida auris, an emerging multidrug-resistant fungal "superbug" responsible for severe hospital outbreaks and high-mortality infections. Our previous proof-of-concept studies in Candida albicans and Candida glabrata established that fungal BET bromodomains – chromatin-binding modules that recognize acetylated histones – represent promising new antifungal targets. We have developed an advanced set of molecular and cellular tools to accelerate antifungal BET inhibitor discovery, including FRET-based assays for compound screening, humanized Candida strains for on-target validation, and NanoBiT assays to monitor BET bromodomain inhibition directly in fungal cells.
This PhD project represents the translational next phase of our research program. It will exploit the AI-guided V-SYNTHES drug discovery approach – a cutting-edge virtual screening and design framework – to develop highly potent BET inhibitors targeting C. auris. Inhibitors will be profiled in biophysical, biochemical and cellular assays, structurally characterized in complex with their bromodomain targets, and validated for on-target activity in C. auris and antifungal efficacy in animal infection models. They will also be used to explore the emergence of resistance to BET inhibition. This project combines an original antifungal strategy with an innovative methodological approach, offering a unique framework for training in interdisciplinary and translational research.
The combined effects of hypoxia and matrix stiffness on the pathophysiology of pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal lung disease characterized by excessive extracellular matrix (ECM) deposition, increased tissue stiffness, and localized hypoxia. These alterations disrupt cell–cell interactions within the alveolo-capillary barrier and drive fibrotic progression. This project aims to investigate, under controlled in vitro conditions, the combined impact of mechanical stiffness and hypoxic stress on the fate and phenotype of pulmonary cell types and their intercellular communication. To achieve this, biomimetic polyacrylamide hydrogels with tunable stiffness and specific ECM protein coatings will be developed to support the co-culture of alveolar epithelial cells, endothelial cells, fibroblasts, and macrophages. Cellular responses will be assessed through proteomics, imaging, and secretome profiling. The goal is to identify key mechano- and chemo-dependent pro-fibrotic factors, providing new insights into IPF pathogenesis and opening avenues for targeted therapeutic strategies and lung tissue regeneration.
Studying the structural dynamics of vitamin B12 -dependent photoreceptors in view of biotechnological applications
This integrated structural biology project aims at gaining a mechanistic understanding of the recently discovered family of vitamin B12 -dependent photoreceptors. In particular, we aim at visualising protein conformational changes upon photoactivation from the photochemical timescales (femtoseconds) to the photobiological timescales (milliseconds -seconds). To do so, we will use time-resolved X-ray crystallography and X-ray solution scattering at X-ray free electron lasers (XFEL) and at synchrotrons. By establishing the modus operandi of these newly discovered B12 photoreceptors we will open a window to their rational modification for biotechnological exploitation as optogenetic components.