Investigating Caspase 4 and Toll-like Receptor 4 Modulation by Endogenous Cardiolipin in Health and Barth Syndrome

Description du projet

Comprendre les processus inflammatoires du syndrome de Barth

Le syndrome de Barth (BTHS) se caractérise par un faible taux de cardiolipine (CL) mitochondriale insaturée et un taux élevé de CL saturée. Cet état entraîne une inflammation chronique et un risque accru d’infection, ce qui contribue à la mortalité des patients. La CL insaturée inhibe normalement la caspase 4 (CASP4) et le récepteur de type Toll 4 (TLR4), qui jouent un rôle crucial dans la défense immunitaire. Cependant, la CL anormale du BTHS n’inhibe pas la CASP4 et active le TLR4, ce qui perturbe la régulation immunitaire et provoque un dysfonctionnement. Soutenu par le programme Actions Marie Skłodowska-Curie, le projet CL-ImmunoDimmer étudiera comment l’appauvrissement en CL des monocytes et des macrophages affecte l’activation de la CASP4 et du TLR4. Il analysera également les marqueurs inflammatoires chez les patients atteints du BTHS, en se concentrant sur les réponses immunitaires des neutrophiles, des monocytes et des macrophages.

Objectif

Barth Syndrome (BTHS) is a disease characterised by reduced production of unsaturated mitochondrial cardiolipin (CL) and increased production of abnormal CL with saturated chains. Chronic inflammation and increased vulnerability to infection are major contributors to mortality in BTHS patients. The connection between these immune dysfunctions and CL modifications is not understood. My research has shown that unsaturated CL inhibits caspase 4 (CASP4) and Toll-like Receptor 4 (TLR4). Moderate CASP4 and TLR4 activation by bacterial triggers is essential for antibacterial defence, while uncontrolled activation results in infection lethality and inflammatory disease. My preliminary data show that abnormal CL similar to the one found in BTHS patients does not inhibit CASP4, and saturated CL activates TLR4. These findings suggest that in health, unsaturated CL acts as a dimmer to fine-tune immune reactions, while in BTHS, this dimmer is compromised, resulting in immune dysfunction. To investigate this hypothesis, this proposal ideally combines my expertise in cardiolipin and mitochondria research with the host’s expertise in gene editing and live microscopy. Using well-established methodologies, we will deplete CL from monocytes and macrophages and study how this affects CASP4 and TLR4 activation. Moreover, I will characterise BTHS immune response through the analysis of inflammatory markers in patients’ plasma, and patients’ neutrophils, monocytes and macrophages CASP4 and TLR4 response. This will provide a deeper mechanistic understanding of inflammatory processes in both health and disease, potentially identifying CL, CASP4, and TLR4 as new targets for treating BTHS. While I will enhance the team’s multidisciplinary character and provide collaboration opportunities, I will be trained in cutting-edge techniques and get leadership and network opportunities crucial for my long-term goal of scientific independence.