Dataset Information

Aspergillus fumigatus-derived gliotoxin impairs innate immune cell activation through modulating lipid mediator production in macrophages

ABSTRACT: Gliotoxin (GT), a major secondary metabolite and virulence factor of Aspergillus fumigatus, suppresses innate immunity and supports the evasion of host immune responses. Recently, we revealed that GT blocks leukotriene (LT)B4 formation by directly inhibiting LTA4 hydrolase (LTA4H) in activated human neutrophils and monocytes. Here, we elucidated the impact of GT on LTB4 biosynthesis and the complex lipid mediator network in human M1- and M2-like monocyte-derived macrophage (MDM) subtypes and studied the respective consequences for innate immune cell functions. Notably, in resting MDMs, GT elicited prostaglandin and 12/15-lipoxygenase product formation, although less efficient than bacterial exotoxins. In activated MDM, LTB4 formation was effectively suppressed by GT, connected to impaired macrophage phagocytic activity, and detrimental consequences for neutrophil movement and migration. Conclusively, GT impairs functions of activated innate immune cells through suppression of LTB4 formation, while GT may prime the immune system by provoking prostaglandin formation and 12/15-lipoxygenase-derived LM.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): M2 Macrophage, M1 Macrophage

SUBMITTER: Thomas Krüger

LAB HEAD: Axel A. Brakhage

PROVIDER: PXD045819 | Pride | 2024-11-13

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	LFQ-Gliotoxin-M1M2.fasta	Fasta
	LFQ-Gliotoxin-M1M2.mgf	Mgf
	LFQ-Gliotoxin-M1M2.msf	Msf
	LFQ-Gliotoxin-M1M2.pdResult	Other
	LFQ-Gliotoxin-M1M2.pep.xml	Pepxml

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Publications

Aspergillus fumigatus-derived gliotoxin impacts innate immune cell activation through modulating lipid mediator production in macrophages.

Günther Kerstin K Nischang Vivien V Cseresnyés Zoltan Z Krüger Thomas T Sheta Dalia D Abboud Zahraa Z Heinekamp Thorsten T Werner Markus M Kniemeyer Olaf O Beilhack Andreas A Figge Marc Thilo MT Brakhage Axel A AA Werz Oliver O Jordan Paul M PM

Immunology 20240913 4

Gliotoxin (GT), a secondary metabolite and virulence factor of the fungal pathogen Aspergillus fumigatus, suppresses innate immunity and supports the suppression of host immune responses. Recently, we revealed that GT blocks the formation of the chemotactic lipid mediator leukotriene (LT)B4 in activated human neutrophils and monocytes, and in rodents in vivo, by directly inhibiting LTA4 hydrolase. Here, we elucidated the impact of GT on LTB4 biosynthesis and the ...[more]

PMID: 39268960

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Project description:Aspergillus fumigatus can cause Invasive Pulmonary Aspergillosis (IPA), the most severe form of Aspergillus-related infections. Fungicidal azoles and fungistatic caspofungin (CAS) are the first- and second-line therapies, respectively, used to treat IPA. However, azole-resistance is on the rise and new therapeutic alternatives need to be implemented. Recently, we showed that treatment of A. fumigatus with CAS or micafungin, but not voriconazole, induces production of the oxylipin 5,8-diHODE by the fungal oxygenase PpoA. Here we investigated the influence of ppo genes, that encode fatty acid oxygenases responsible for oxylipin biosynthesis, on CAS tolerance. The ppo mutants showed a very complex pattern of CAS susceptibility. PpoA and PpoC influence on CAS tolerance is mediated by MpkA phosphorylation and protein kinase A (PKA) activity. RNAseq transcriptional profiling and label-free quantitative proteomics (spectral counts) of the ppoA, and ppoC mutants showed that differentially expressed genes and proteins are related to secondary metabolites and carbohydrate metabolism. We tested several mutants of these differentially expressed genes encoding transcription factors and signal transduction proteins and some of them are more susceptible to CAS. We also characterized two clinical isolates, CNM7555 and IFM41607, that have decreased and increased susceptibility to CAS. CNM7555 does not have increased oxylipin production in the presence of CAS while the oxylipin induction upon CAS exposure is increased in the IFM41607, suggesting oxylipins are not the single mechanism involved in CAS tolerance in these isolates. Upon CAS exposure, CNM7555 has increased MpkA phosphorylation and PKA activity than IFM41607. Modulation of secondary metabolite production and carbohydrate metabolism is also essential in these clinical isolates for acquiring CAS tolerance. Our results reveal different aspects and genetic determinants involved in A. fumigatus CAS tolerance.