METAFUN · Metabolic control of immune cell function during fungal infection

The high mortality rates and healthcare costs associated with severe fungal infections highlight the urgent need to unveil their pathogenetic mechanisms and develop more effective diagnosis and treatment measures. Innate immunity has a key role in host response to fungal infection, by mediating fungal recognition and elimination, and modulating adaptive immune responses. The long pentraxin PTX3 is a soluble pattern recognition receptor that is involved in the recognition and opsonisation of Aspergillus fumigatus. Metabolism is a central regulator of immune cell function. Phagocytosis of A. fumigatus conidia elicits enhanced glycolysis in macrophages and is essential for optimal antifungal effector functions. Preliminary data from the host lab indicate that PTX3 deficiency, by compromising the metabolic reprogramming of macrophages, impairs phagocytosis, but also their conidiacidal capacity upon infection. Nevertheless, little is known about the mechanistic bases linking the functional activity of PTX3 and immune cell metabolism in the pathogenesis of fungal infection. In METAFUN, we propose to (i) define the molecular and cellular mechanisms whereby PTX3 regulates immune cell metabolism, (ii) dissect the spatiotemporal contribution of PTX3 to intracellular mechanisms of fungal clearance, and (iii) evaluate the contribution of PTX3 to fungicidal mechanisms in a human disease-relevant context using lung-on-a-chip systems. This original and interdisciplinary project will reveal previously unanticipated functions of PTX3 in antifungal immunity and will lay the foundations for the identification of new diagnostic and therapeutic targets for fungal disease.