Project 2

Lundquist Institute For Biomedical Innovation At Harbor-Ucla Medical Center, Torrance CA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Mucormycosis (MCM) affects an expanding range of patients with unique immunometabolic abnormalities. Un- derstanding the molecular mechanisms of host-fungal metabolic interplay is an unmet priority for development of new therapeutic approaches against MCM. Professional phagocytes, mainly alveolar macrophages (AMs) and neutrophils, confer sterilizing immunity against Mucorales via unknown host effector mechanisms targeting the pathogenetic program of the fungus. Germinating Mucorales spores can evade these immune responses through expression of virulence factors such as mucoricin and other mycotoxins. We discovered that albumin-bound free fatty acids (FFAs) specifically inhibit Mucorales spores at the extracel- lular space by targeting fungal aerobic glycolysis and mucoricin expression. FFAs stored in lipid droplets of AMs also inhibit fungal spores following their uptake, upon immunometabolic sensing of fungal melanin. Bioactive lipids produced by the activity of cytosolic phospholipase 2 (cPLA2) orchestrate neutrophils clustering (swarming) to eliminate germinating spores that escape from AM surveillance. Collectively, our data put forward a new model of the immune response against Mucorales with profound implications in MCM pathogenesis. In this model, lipid metabolism is the central orchestrator of sequential lines of host defense against Mucorales. We propose to identify: 1) the master regulators of the host-Mucorales metabolic interplay that occurs after spores taken up by AMs, at the cellular and molecular level. In parallel, we will prioritize evaluation of novel immunometabolic therapies against MCM that are tailored to restore defects in lipid metabolism of AMs (e.g., HiF1α inhibitors, lipid lowering drugs) (Aim1); 2) the mechanism of activation and functional role of cPLA2 in neutrophil swarming against germinating Mucorales that evade AM surveillance and the effect of fungal mole- cules (e.g., cell wall polysaccharides, toxins) in shaping this process, physiologically and in the disease models of MCM. We will evaluate immunomodulators that promote neutrophil swarming (e.g., GM-CSF). We will also evaluate inhibition of fungal pathogenetic program (e.g., mycotoxin production) by nutritional immunity (e.g., 2 deoxyglucose, albumin) as a strategy to harness neutrophil swarming in physiologically relevant MCM models of our collaborators (Aim2); and 3) further analyze the physiological relevance of novel immunometabolic re- sponses against Mucorales in Aim1 and Aim2, in unique phagocyte subsets of patients with MCM, and validate the use of mechanistically interconnected unique host serum metabolites (e.g., albumin, oxylipins) as novel bi- omarkers of MCM in human patients (Aim3). Our collaborative efforts will identify the central regulators of host-fungal immunometabolic cross talk and eval- uate clinically relevant diagnostic and therapeutic metabolic targets for MCM. These findings will transform our understanding on MCM pathogenesis, resulting in a paradigm shift in management of this devastating disease.