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

Descrizione del progetto

Comprendere i processi infiammatori della sindrome di Barth

La sindrome di Barth (BTHS) è caratterizzata da bassi livelli di cardiolipina mitocondriale insatura (CL) e da un aumento di quella satura. Questa condizione porta a un’infiammazione cronica e a un aumento del rischio di infezione, contribuendo alla mortalità dei pazienti. Normalmente, la CL insatura inibisce la caspasi 4 (CASP4) e il recettore toll-like 4 (TLR4), fondamentale per la difesa immunitaria. Nella BTHS, invece, la CL anomala non inibisce la CASP4 e attiva il TLR4, compromettendo la regolazione immunitaria e causando disfunzioni. Con il sostegno del programma di azioni Marie Skłodowska-Curie, il progetto CL-ImmunoDimmer studierà come la deplezione della CL dai monociti e dai macrofagi influisca sull’attivazione di CASP4 e TLR4. Verranno inoltre analizzati i marcatori infiammatori nei pazienti con BTHS, concentrandosi sulle risposte immunitarie di neutrofili, monociti e macrofagi.

Obiettivo

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.