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

IF 4.2 2区生物学 Q2 MICROBIOLOGY

Journal of Fungi Pub Date : 2024-10-30 DOI:10.3390/jof10110749

Endrews Delbaje, Patrícia Alves de Castro, Dante G Calise, Niu Mengyao, Maria Augusta Crivelente Horta, Daniel Yuri Akiyama, João Guilherme Pontes, Taícia Fill, Olaf Kniemeyer, Thomas Krüger, Axel A Brakhage, Koon Ho Wong, Nancy P Keller, Gustavo H Goldman

{"title":"The Influence of Aspergillus fumigatus Fatty Acid Oxygenases PpoA and PpoC on Caspofungin Susceptibility.","authors":"Endrews Delbaje, Patrícia Alves de Castro, Dante G Calise, Niu Mengyao, Maria Augusta Crivelente Horta, Daniel Yuri Akiyama, João Guilherme Pontes, Taícia Fill, Olaf Kniemeyer, Thomas Krüger, Axel A Brakhage, Koon Ho Wong, Nancy P Keller, Gustavo H Goldman","doi":"10.3390/jof10110749","DOIUrl":null,"url":null,"abstract":"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.","PeriodicalId":15878,"journal":{"name":"Journal of Fungi","volume":"10 11","pages":""},"PeriodicalIF":4.2000,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11595811/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Fungi","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.3390/jof10110749","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MICROBIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

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.

查看原文本刊更多论文

曲霉脂肪酸加氧酶 PpoA 和 PpoC 对卡泊芬净敏感性的影响

烟曲霉菌可引起侵袭性肺曲霉菌病（IPA）。杀真菌的唑类和杀真菌的卡泊芬净（CAS）分别是治疗 IPA 的一线和二线疗法。用 CAS 或米卡芬净治疗烟曲霉菌可诱导真菌加氧酶 PpoA 产生 5,8-diHODE 氧脂素。在本文中，我们研究了编码负责氧脂素生物合成的脂肪酸加氧酶的 ppo 基因对 CAS 耐受性的影响。PpoA 和 PpoC 对 CAS 耐受性的影响是由 MpkA 磷酸化和蛋白激酶 A（PKA）活性介导的。ppoA和ppoC突变体的RNAseq转录谱分析和无标记定量蛋白质组学研究表明，差异表达的基因和蛋白质与次生代谢产物和碳水化合物代谢有关。我们还鉴定了 CM7555 和 IFM61407 这两种临床分离株，它们对 CAS 的敏感性分别降低和提高。在 CAS 存在的情况下，CM7555 并未表现出氧脂素生成增加，但 IFM61407 在接触 CAS 后氧脂素诱导增加，这表明氧脂素并不是这些分离物耐受 CAS 的唯一机制。暴露于 CAS 时，CM7555 的 MpkA 磷酸化和 PKA 活性高于 IFM61407。我们的研究结果揭示了烟曲霉耐受 CAS 的不同方面和遗传决定因素。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Journal of Fungi Medicine-Microbiology (medical)

CiteScore

6.70

自引率

14.90%

发文量

1151

审稿时长

11 weeks

期刊介绍： Journal of Fungi (ISSN 2309-608X) is an international, peer-reviewed scientific open access journal that provides an advanced forum for studies related to pathogenic fungi, fungal biology, and all other aspects of fungal research. The journal publishes reviews, regular research papers, and communications in quarterly issues. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. Therefore, there is no restriction on paper length. Full experimental details must be provided so that the results can be reproduced.