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.
Exploring mechanisms of action of vaccine induced protection against infectious diseases in humans
The project aims at unravelling the molecular and cellular mechanisms that contribute to long-term protection induced by vaccines. Early changes (hours and days) occurring at site of injection and distant sites following vaccine injection will be correlated to long lasting (beyond 12 months) induction of neutralizing antibodies and specific T and B cell memory. A particular focus will be made to the relation of immune response with vaccine antigen persistence in the organisms. Multiple omics approaches will be applied to different tissue compartments of animals vaccinated with the yellow fever vaccine (Stamaril) known to induce a remarkable durable response, to then inform the design of new generation of anti-poxvirus vaccines.