Project description
Understanding invasive mould infections
The prevalence of respiratory diseases due to airborne filamentous fungi is on the rise. Invasive mould infections (IMI) are associated with high mortality rates in patients, necessitating more effective treatment options. The EU-funded iMAC-FUN project proposes an innovative mechanism to evaluate the pathogenesis of IMI, based on the use of moulds as model pathogens. It will analyse the role of selected ferric reductases in infection, detect novel iron transporters involved in host defence and explore mechanisms of melanin interference with iron regulation in macrophages. It will then apply a solid, objective method based on the combination of transcriptomics, metalloproteomics, in vivo RNAi screening in the Drosophila model of IMI and validation studies in transgenic mice and ultimately in human patients ex vivo.
Objective
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.
Fields of science
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
70013 Irakleio
Greece