1. Academic Validation
  2. Candida albicans-induced leukotriene biosynthesis in neutrophils is restricted to the hyphal morphology

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

  • FASEB J. 2021 Oct;35(10):e21820. doi: 10.1096/fj.202100516RR.
Jana Fischer 1 2 Mark S Gresnigt 3 Oliver Werz 2 Bernhard Hube 4 5 Ulrike Garscha 1 2
Affiliations

Affiliations

  • 1 Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Greifswald University, Greifswald, Germany.
  • 2 Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany.
  • 3 Junior Research Group Adaptive Pathogenicity Strategies, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute, Jena, Germany.
  • 4 Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute, Jena, Germany.
  • 5 Institute of Microbiology, Friedrich Schiller University Jena, Jena, Germany.
Abstract

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.

Keywords

5-lipoxygenase; fungi; immune response; inflammation; lipid mediator; oxylipins.

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