Descripción del proyecto
Comprender las infecciones fúngicas invasoras
La prevalencia de las enfermedades respiratorias causadas por hongos filamentosos transmitidos por el aire va en aumento. Las infecciones fúngicas invasoras (IFI) están relacionadas con la elevada tasa de mortalidad en los pacientes, lo que hace que sean necesarias opciones de tratamiento más efectivas. El proyecto iMAC-FUN, financiado con fondos europeos, propone un mecanismo innovador, basado en el uso de mohos como patógenos modelo para evaluar la patogenia de las IFI. Evaluará el papel de determinadas reductasas férricas en la infección, detectará nuevos transportadores de hierro involucrados en la defensa del hospedador y explorará los mecanismos de interferencia de la melanina con la regulación del hierro en los macrófagos. Para continuar, aplicará un método sólido y objetivo basado en la combinación de la transcriptómica, la metaloproteómica, el cribaje de ARNi «in vivo» en el modelo de «Drosophila melanogaster» de IFI y estudios de validación en ratones transgénicos y, finalmente, en pacientes humanos «ex vivo».
Objetivo
Airborne filamentous fungi (molds) are major causes of respiratory diseases in an expanding population of patients with complex immune and metabolic defects. Invasive mold infections (IMI) are associated with substantial mortality and enormous economic impact. Understanding pathogenesis of IMI is an unmet need for design of better therapies. We have put forward a novel mechanism for the pathogenesis of IMI, according to which development of IMI requires two discrete mechanisms (a) phagosome maturation arrest via inhibition of LC3-associated phagocytosis (LAP), which allows intracellular persistence of fungal conidia (spores), and (b) alteration in iron homeostasis, resulting in invasive fungal growth and lysis of the macrophage. On the pathogen site, fungal melanin targets LAP and affects macrophage metal homeostasis. On the macrophage site, iron distribution in subcellular compartments of all eukaryotic cells is controlled by ferric reductases and divalent cation transporters, in a process that remains molecularly unexplored. During mold infection a group of ferric reductases represent the most prominently transcriptionally modulated iron regulatory genes in macrophages. Thus, iron regulation is the critical determinant of macrophage-fungal interplay and is the focus of this project. We will use molds as model pathogens to (i) dissect the role of selected ferric reductases in infection, (ii) identify novel iron transporters implicated in host defense (iii) and explore mechanisms of melanin interference with iron regulation in macrophages. To this end, we will employ a robust, unbiased, approach combining transcriptomics, metalloproteomics, in vivo RNAi screening in Drosophila model of IMI, and validation studies in transgenic mice and eventually in human patients ex vivo. Dissecting the function of novel iron regulators in the macrophage will have profound impact on iron biology and is likely to have direct therapeutic implications for the management of IMI.
Ámbito científico
Programa(s)
Régimen de financiación
ERC-COG - Consolidator GrantInstitución de acogida
70013 Irakleio
Grecia