Candida albicans-induced leukotriene biosynthesis in neutrophils is restricted to the hyphal morphology

Neutrophils are the most abundant leukocytes in circulation playing a key role in acute inflammation during microbial infections. Phagocytosis, one of the crucial defence mechanisms of neutrophils against pathogens, is amplified by chemotactic leukotriene (LT)B₄ , which is biosynthesized via 5-lipoxygenase (5-LOX). However, extensive liberation of LTB₄ can be destructive by over-intensifying the inflammatory process. While enzymatic biosynthesis of LTB₄ is well characterized, less is known about molecular mechanisms that activate 5-LOX and lead to LTB₄ formation during host-pathogen interactions. Here, we investigated the ability of the common opportunistic fungal pathogen Candida albicans to induce LTB₄ formation in neutrophils, and elucidated pathogen-mediated drivers and cellular processes that activate this pathway. We revealed that C. albicans-induced LTB₄ biosynthesis requires both the morphological transition from yeast cells to hyphae and the expression of hyphae-associated genes, as exclusively viable hyphae or yeast-locked mutant cells expressing hyphae-associated genes stimulated 5-LOX by [Ca²⁺ ]_i mobilization and p38 MAPK activation. LTB₄ biosynthesis was orchestrated by synergistic activation of dectin-1 and Toll-like receptor 2, and corresponding signaling via SYK and MYD88, respectively. Conclusively, we report hyphae-specific induction of LTB₄ biosynthesis in human neutrophils. This highlights an expanding role of neutrophils during inflammatory processes in the response to C. albicans infections.