The Influence of Aspergillus fumigatus Fatty Acid Oxygenases PpoA and PpoC on Caspofungin Susceptibility

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Delbaje, Endrews ; de Castro, Patricia Alves ; Calise, Dante G. ; Mengyao, Niu ; Horta, Maria Augusta Crivelente ; Akiyama, Daniel Yuri ; Pontes, Joao Guilherme ; Fill, Taicia ; Kniemeyer, Olaf ; Kruger, Thomas ; Brakhage, Axel A. ; Wong, Koon Ho ; Keller, Nancy P. ; Goldman, Gustavo H.

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF FUNGI; v. 10, n. 11, p. 23-pg., 2024-11-01.

Resumo

Aspergillus fumigatus can cause invasive pulmonary aspergillosis (IPA). Fungicidal azoles and fungistatic caspofungin (CAS) are the first- and second-line therapies, respectively, used to treat IPA. Treatment of A. fumigatus with CAS or micafungin induces the production of the oxylipin 5,8-diHODE by the fungal oxygenase PpoA. For this article, we investigated the influence of ppo genes, which encode the fatty acid oxygenases responsible for oxylipin biosynthesis, on CAS tolerance. The influence of PpoA and PpoC on CAS tolerance is mediated by MpkA phosphorylation and protein kinase A (PKA) activity. RNAseq transcriptional profiling and the label-free quantitative proteomics of the ppoA and ppoC mutants showed that differentially expressed genes and proteins are related to secondary metabolites and carbohydrate metabolism. We also characterized two clinical isolates, CM7555 and IFM61407, which decrease and increase susceptibility to CAS, respectively. CM7555 does not exhibit increased oxylipin production in the presence of CAS but oxylipin induction upon CAS exposure is increased in IFM61407, suggesting that oxylipins are not the only mechanism involved in CAS tolerance in these isolates. Upon CAS exposure, CM7555 has higher MpkA phosphorylation and PKA activity than IFM61407. Our results reveal the different aspects and genetic determinants involved in A. fumigatus CAS tolerance. (AU)

• Processo FAPESP: 23/00206-0 - Caracterização de mitogenomas de populações de Aspergillus fumigatus com cepas resistentes e suscetíveis a drogas antifúngicas
• Beneficiário: Endrews Delbaje
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 22/02992-0 - Decifrando o papel de metabólitos secundários na interação química entre fitopatógenos e o hospedeiro citros
• Beneficiário: Taicia Pacheco Fill
• Modalidade de apoio: Auxílio à Pesquisa - Projeto Inicial
• Processo FAPESP: 21/04977-5 - A identificação de vias metabólicas e compostos químicos que podem potenciar a ação de caspofungin contra Aspergillus fumigatus
• Beneficiário: Gustavo Henrique Goldman
• Modalidade de apoio: Auxílio à Pesquisa - Temático