Fungal melanin induces host lipid defense by rewiring macrophage metabolism

Abstract Alveolar macrophages (AMs) employ specialized immunometabolic programs to counteract virulence mechanisms of airborne pathogens and confer host protection1. Mucormycosis is a life-threatening respiratory fungal infection that predominantly affects patients with metabolic abnormalities, especially diabetic ketoacidosis (DKA) 2, through poorly defined mechanisms. Unlike other fungi, Mucorales induce phagosome maturation arrest in AMs through persistent surface expression of melanin3,4, yet the host defense mechanisms that restrict fungal growth remain uncharacterized. Herein, we found that phagocytosis of Mucorales spores triggers the selective recruitment of Lipid Droplets (LDs) to the phagosome, through metabolic reprograming of AM metabolism toward oxidative phosphorylation (OXPHOS). Ca2+ sequestration by fungal melanin triggers this immunometabolic response in AMs by modulating mitochondria dynamics. LD targeting results in robust accumulation of host free fatty acids (FFAs) within intracellular Mucorales spores, leading to rapid mitochondrial fragmentation, suppression of aerobic glycolysis and fungal growth arrest. In DKA, nuclear stabilization of HIF1 inhibits mitochondrial function and OXPHOS-dependent LD targeting to the phagosome to promote fungal disease. Pharmacological inhibition or conditional deletion of HIF1 in AMs restores OXPHOS and protects against mucormycosis. Collectively, our findings define a melanin-driven immunometabolic defense program and reveal host and fungal metabolic vulnerabilities with important implications in pathogenesis and treatment of mucormycosis.