A multidimensional assessment of in-host fitness costs of drug resistance in the opportunistic fungal pathogen Candida glabrata.

IF 2.4 4区 生物学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Amir Arastehfar, Farnaz Daneshnia, Hrant Hovhannisyan, Nathaly Cabrera, Macit Ilkit, Jigar V Desai, Toni Gabaldón, Erika Shor, David S Perlin
{"title":"A multidimensional assessment of in-host fitness costs of drug resistance in the opportunistic fungal pathogen Candida glabrata.","authors":"Amir Arastehfar, Farnaz Daneshnia, Hrant Hovhannisyan, Nathaly Cabrera, Macit Ilkit, Jigar V Desai, Toni Gabaldón, Erika Shor, David S Perlin","doi":"10.1093/femsyr/foae035","DOIUrl":null,"url":null,"abstract":"<p><p>Drug-resistant microbes typically carry mutations in genes involved in critical cellular functions and may therefore be less fit under drug-free conditions than susceptible strains. Candida glabrata is a prevalent opportunistic yeast pathogen with a high rate of fluconazole resistance (FLZR), echinocandin resistance (ECR), and multidrug resistance (MDR) relative to other Candida. However, the fitness of C. glabrata MDR isolates, particularly in the host, is poorly characterized, and studies of FLZR isolate fitness have produced contradictory findings. Two important host niches for C. glabrata are macrophages, in which it survives and proliferates, and the gut. Herein, we used a collection of clinical and lab-derived C. glabrata isolates to show that FLZR C. glabrata isolates are less fit inside macrophages than susceptible isolates and that this fitness cost is reversed by acquiring ECR mutations. Interestingly, dual-RNAseq revealed that macrophages infected with drug-resistant isolates mount an inflammatory response whereas intracellular drug-resistant cells downregulate processes required for in-host adaptation. Furthermore, drug-resistant isolates were outcompeted by their susceptible counterparts during gut colonization and in infected kidneys, while showing comparable fitness in the spleen. Collectively, our study shows that macrophage-rich organs, such as the spleen, favor the retention of MDR isolates of C. glabrata.</p>","PeriodicalId":12290,"journal":{"name":"FEMS yeast research","volume":" ","pages":""},"PeriodicalIF":2.4000,"publicationDate":"2024-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11631428/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"FEMS yeast research","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1093/femsyr/foae035","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Drug-resistant microbes typically carry mutations in genes involved in critical cellular functions and may therefore be less fit under drug-free conditions than susceptible strains. Candida glabrata is a prevalent opportunistic yeast pathogen with a high rate of fluconazole resistance (FLZR), echinocandin resistance (ECR), and multidrug resistance (MDR) relative to other Candida. However, the fitness of C. glabrata MDR isolates, particularly in the host, is poorly characterized, and studies of FLZR isolate fitness have produced contradictory findings. Two important host niches for C. glabrata are macrophages, in which it survives and proliferates, and the gut. Herein, we used a collection of clinical and lab-derived C. glabrata isolates to show that FLZR C. glabrata isolates are less fit inside macrophages than susceptible isolates and that this fitness cost is reversed by acquiring ECR mutations. Interestingly, dual-RNAseq revealed that macrophages infected with drug-resistant isolates mount an inflammatory response whereas intracellular drug-resistant cells downregulate processes required for in-host adaptation. Furthermore, drug-resistant isolates were outcompeted by their susceptible counterparts during gut colonization and in infected kidneys, while showing comparable fitness in the spleen. Collectively, our study shows that macrophage-rich organs, such as the spleen, favor the retention of MDR isolates of C. glabrata.

对机会性真菌病原体格拉布氏念珠菌耐药性的宿主内部健康成本进行多维评估
耐药微生物通常携带涉及关键细胞功能的基因突变,因此在无药条件下可能不如易感菌株适应。格拉布氏念珠菌是一种流行的机会性酵母病原体,与其他念珠菌相比,它对氟康唑耐药(FLZR)、对棘白菌素耐药(ECR)和对多种药物耐药(MDR)的比率很高。然而,格氏念珠菌 MDR 分离物的适应性,尤其是在宿主中的适应性,还没有得到很好的描述,而对 FLZR 分离物适应性的研究也得出了相互矛盾的结果。对于草履蛆来说,两个重要的宿主龛位是巨噬细胞和肠道,草履蛆在巨噬细胞中存活并增殖。在本文中,我们使用了一系列临床和实验室来源的玻璃疽分离株,结果表明 FLZR 玻璃疽分离株与易感分离株相比,在巨噬细胞内的适应性较差,而这种适应性成本可通过获得 ECR 突变而逆转。有趣的是,双 RNAseq 发现,感染了耐药分离株的巨噬细胞会产生炎症反应,而细胞内的耐药细胞则会下调宿主内适应所需的过程。此外,耐药分离株在肠道定植过程中和在受感染的肾脏中被易感分离株竞争,而在脾脏中则表现出相当的适应性。总之,我们的研究表明,富含巨噬细胞的器官(如脾脏)有利于MDR分离株的存留。
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
FEMS yeast research
FEMS yeast research 生物-生物工程与应用微生物
CiteScore
5.70
自引率
6.20%
发文量
54
审稿时长
1 months
期刊介绍: FEMS Yeast Research offers efficient publication of high-quality original Research Articles, Mini-reviews, Letters to the Editor, Perspectives and Commentaries that express current opinions. The journal will select for publication only those manuscripts deemed to be of major relevance to the field and generally will not consider articles that are largely descriptive without insights on underlying mechanism or biology. Submissions on any yeast species are welcome provided they report results within the scope outlined below and are of significance to the yeast field.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信