Descrizione del progetto
Comprendere le infezioni invasive da muffe
La prevalenza delle malattie respiratorie dovute a funghi filamentosi aerei è in aumento. Le infezioni invasive da muffe (invasive mould infections, IMI) sono associate ad alti tassi di mortalità nei pazienti e necessitano perciò di opzioni di trattamento più efficaci. Il progetto iMAC-FUN, finanziato dall’UE, propone un meccanismo innovativo per valutare la patogenesi delle IMI, sulla base dell’uso di muffe come agenti patogeni modello. Il progetto analizzerà il ruolo di ferrico-reduttasi selezionati in infezione, individuerà nuovi trasportatori di ferro coinvolti nella difesa dell’ospite ed esplorerà meccanismi di interferenza della melanina con la regolazione del ferro nei macrofagi. Applicherà poi un metodo solido e obiettivo basato sulla combinazione di trascrittomica, metalloproteomica, screening dell’RNAi in vivo nel modello di Drosophila delle IMI e studi di convalida in topi transgenici e, alla fine, in pazienti umani ex vivo.
Obiettivo
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.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
70013 Irakleio
Grecia