Fungal lipase LipA disarms macrophages by remodeling their lipidome, enabling full virulence in immunocompetent hosts.

Aspergillus fumigatus is an opportunistic fungal pathogen that causes invasive pulmonary aspergillosis, particularly in immunocompromised individuals. Here, we identify LipA, a secreted lipase enriched on the conidial surface that modulates host immunity and is essential for full pathogenicity in immunocompetent hosts. Upon macrophage exposure, ΔlipA is phagocytosed more readily, reducing conidial viability and pro-inflammatory cytokine production. Comparative lipidomics revealed that LipA actively remodels the host macrophage lipidome, depleting complex ether-linked phospholipids and polyunsaturated fatty acid (PUFA) reservoirs, while promoting free fatty acid accumulation. LipA deprives host phospholipase A2 of substrates needed for pro-inflammatory eicosanoid production and modulates sphingolipid metabolism by shifting the balance from pro-apoptotic ceramides to sphingomyelins, thereby promoting host cell survival. These findings show that A. fumigatus LipA is an effector-like molecule that actively disarms host macrophages by remodeling the lipidome, disrupting precursors of inflammatory signaling, degrading immune-activating lipid antigens, and creating a permissive environment for fungal survival.