Periodic Reporting for period 2 - iMAC-FUN (Dissecting novel mechanisms of iron regulation during macrophage-fungal interplay)
Reporting period: 2022-03-01 to 2023-08-31
The iMAC FUN project is exploring physiological mechanisms of iron regulation during interaction of macrophages with airborne saprophytic fungi (molds). Understanding the role of nutritional immunity (iron starvation) during fungal infection and the mechanistic connections with other antifungal pathways is crucial to understand pathogenesis of respiratory disorders caused by these emerging pathogens. Apart from nutritional immunity, the master regulatory role of iron on macrophage metabolism and host defense will be explored in detail. Because fungi trigger unique regulatory programs during daily interaction with lung resident macrophages the iMAC FUN project will discover novel aspects of macrophage biology and metabolism with broad implications.
The iMAC FUN project has already identified a master regulatory role of the cytokine IL-6 in antifungal activity of macrophages with major implications in pathogenesis of immunoparalysis of patients with sepsis (Akoumianaki T et al. Cell Host Microbe 2021; https://pubmed.ncbi.nlm.nih.gov/34214493/). Of interest, IL-6 signaling ensures for the optimal trafficking of intracellular cargo for the optimal elimination of phagocytosed fungal spores via activation of a specialized host defense pathway termed LC3 associated phagocytosis (LAP). Defects in IL-6 signaling induced by sepsis, corticosteroids or targeted immunomodulatory therapies (e.g. monoclonal antibodies targeting IL-6 or JAK/STAT inhibitors) utilized for dampening of inflammation induced by COVID or autoimmune disorders, compromises essential antifungal functions of macrophages and results in heightened susceptibility for respiratory fungal disease.
Ongoing work is exploring the role of nutritional immunity via iron restriction inside the macrophage in the setting of genetic or inducible defects in activation of LAP. Parallel work is exploring potential links of iron metabolism in activation of the LAP pathway and the role of divalent cation transporters in this process. Finally, in parallel projects we characterize the role of LAP-independent antifungal pathways regulated by iron and macrophage metabolism. Collectively, our work will identify novel mechanisms of cross talk of iron with macrophage metabolism and antimicrobial host defense in health and disease.
The overall goal of this work is to provide a comprehensive view of macrophage biology during fungal infection and the critical role of iron in orchestrating this process. Our approach will pave the way for novel biological measures of macrophage function and related tools to stratify immunoparalysis and susceptibility for invasive fungal disease. In addition, our work will pave the way for novel host-directed therapeutic strategies harnessing macrophage metabolism to restore immune defects
The overall goal of this work is to provide a comprehensive view of macrophage biology during fungal infection and the critical role of iron in orchestrating this process. Our approach will pave the way for novel biological measures of macrophage function and related tools to stratify immunoparalysis and susceptibility for invasive fungal disease. In addition, our work will pave the way for novel host-directed therapeutic strategies harnessing macrophage metabolism to restore immune defects