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Proteomic analysis of bronchoalveolar lavage fluid during invasive pulmonary aspergillosis in mice and humans

ABSTRACT: Comprehensive proteomic analysis of the protein expression landscape of bronchoalveolar lavage fluid during invasive pulmonary aspergillosis in murine and human samples. 38 murine BALF samples (10 Aspergillus fumigatus infected mice without immunosuppression and without invasive pulmonary aspergillosis (IPA), 19 immunosuppressed and infected mice with IPA and 9 immunosuppressed animals without infection) were analysed for their global protein expression. In addition, 54 human BALF specimen from patients with probable IPA (23 samples), proven IPA (4 cases) and 27 control samples from patients with unrelated pulmonary diseases were analysed for their global protein composition. Host responses and Aspergillus fumigatus-specific proteins detectable in BALF were studied.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Lung, Bronchoalveolar Lavage

DISEASE(S): Invasive Aspergillosis

SUBMITTER: Mario Müller

LAB HEAD: Hortense Slevogt

PROVIDER: PXD016664 | Pride | 2020-10-14

REPOSITORIES: Pride

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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.

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Proteomic analysis of bronchoalveolar lavage fluid during invasive pulmonary aspergillosis in mice and humans

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