Gliotoxin from Aspergillus fumigatus Abrogates Leukotriene B4 Formation through Inhibition of Leukotriene A4 Hydrolase
| Autor: | Kirstin Scherlach, Antonietta Rossi, Anna Proschak, Jan Dworschak, Jan S. Kramer, Axel A. Brakhage, Ewgenij Proschak, Stefanie König, Jana Gerstmeier, Simona Pace, Lidia Sautebin, Helmut Pein, Maria Straßburger, Oliver Werz, Christian Hertweck, Jesper Z. Haeggström, Erik Romp, Fabiana Troisi, Thorsten Heinekamp |
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| Přispěvatelé: | Publica, König, Stefanie, Pace, Simona, Pein, Helmut, Heinekamp, Thorsten, Kramer, Jan, Romp, Erik, Straßburger, Maria, Troisi, Fabiana, Proschak, Anna, Dworschak, Jan, Scherlach, Kirstin, Rossi, Antonietta, Sautebin, Lidia, Haeggström, Jesper Z, Hertweck, Christian, Brakhage, Axel A, Gerstmeier, Jana, Proschak, Ewgenij, Werz, Oliver |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
gliotoxin
Clinical Biochemistry 01 natural sciences Biochemistry Virulence factor Aspergillus fumigatus Microbiology invasive aspergillosi Leukotriene-A4 hydrolase chemistry.chemical_compound neutrophils Immunity Drug Discovery Molecular Biology Pharmacology Leukotriene Innate immune system Gliotoxin biology 010405 organic chemistry leukotriene Chemotaxis biology.organism_classification leukotriene A(4) hydrolase 0104 chemical sciences chemistry Aspergillus fumigatu Molecular Medicine |
| Popis: | The epidithiodioxopiperazine gliotoxin is a virulence factor of Aspergillus fumigatus, the most important airborne fungal pathogen of humans. Gliotoxin suppresses innate immunity in invasive aspergillosis, particularly by compromising neutrophils, but the underlying molecular mechanisms remain elusive. Neutrophils are the first responders among innate immune cells recruited to sites of infection by the chemoattractant leukotriene (LT)B4 that is biosynthesized by 5-lipoxygenase and LTA4 hydrolase (LTA4H). Here, we identified gliotoxin as inhibitor of LTA4H that selectively abrogates LTB4 formation in human leukocytes and in distinct animal models. Gliotoxin failed to inhibit the formation of other eicosanoids and the aminopeptidase activity of the bifunctional LTA4H. Suppression of LTB4 formation by gliotoxin required the cellular environment and/or reducing conditions, and only the reduced form of gliotoxin inhibited LTA4H activity. Conclusively, gliotoxin suppresses the biosynthesis of the potent neutrophil chemoattractant LTB4 by direct interference with LTA4H thereby impairing neutrophil functions in invasive aspergillosis. |
| Databáze: | OpenAIRE |
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