Gliotoxin from Aspergillus fumigatus Abrogates Leukotriene B Formation through Inhibition of Leukotriene A Hydrolase.

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)B that is biosynthesized by 5-lipoxygenase and LTA hydrolase (LTAH). Here, we identified gliotoxin as inhibitor of LTAH that selectively abrogates LTB 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 LTAH. Suppression of LTB formation by gliotoxin required the cellular environment and/or reducing conditions, and only the reduced form of gliotoxin inhibited LTAH activity. Conclusively, gliotoxin suppresses the biosynthesis of the potent neutrophil chemoattractant LTB by direct interference with LTAH thereby impairing neutrophil functions in invasive aspergillosis.