ws08.05铜绿假单胞菌对提取因子/tezacaftor/ivacaftor治疗适应性的多组学研究

IF 5.4 2区医学 Q1 RESPIRATORY SYSTEM

Journal of Cystic Fibrosis Pub Date : 2025-06-01 DOI:10.1016/j.jcf.2025.03.538

L. Veschetti , S. Piccolo , G. Vingiani , C. Paganin , E.V. Fiscarelli , A. Bragonzi , C. Cigana

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引用次数: 0

摘要

目的elexaftor /tezacaftor/ivacaftor （ETI）为囊性纤维化（pwCF）患者提供了显著的临床益处，尽管治疗效果不同，可能是由于个体肺部微生物谱等因素。我们的目标是通过整合表型、转录组学和基因组数据来研究Pa对ETI的反应，以确定适应性性状并了解治疗结果的可变性。方法在开始ETI治疗前和治疗后18个月，从3例pwCF中收集与大肠杆菌相关的分离株。分析了与急性/间歇性感染和慢性定植相关的表型特征。分离株在人工痰液培养基中暴露于ETI或DMSO 6小时，模拟CF痰液条件。对细菌RNA进行测序，转录物进行定量，并进行差异表达（DEA）和途径富集分析。结果表型分析显示菌株依赖性适应，主要影响花青素的产生和生物膜的形成。纵向分离株的DEA显示，跨克隆谱系的调节转录物有少量重叠（上调0.3%，下调0.07%），表明菌株对体内ETI暴露有特异性转录反应。共享的调节转录本与分泌系统、β -内酰胺抗性、ABC转运蛋白和代谢途径有关。体外ETI处理在分离株之间没有引起一致的转录调节，但体外调节的0.6-3.7%的转录本在体内也受到影响，表明ETI直接影响。另外8例pwCF已被招募，全基因组测序正在进行中，以探索病理适应性突变。我们的研究结果表明，暴露于ETI治疗可以以pwcf特异性的方式改变特定的Pa表型性状和转录组，从而深入了解治疗效果的变异性。本研究由意大利CF基金会（ffc# 16/2021）支持。

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WS08.05Multi-omics insights into Pseudomonas aeruginosa’s adaptation to elexacaftor/tezacaftor/ivacaftor therapy

Objectives

Elexacaftor/tezacaftor/ivacaftor (ETI) offers significant clinical benefits for eligible people with cystic fibrosis (pwCF), though treatment effectiveness varies, potentially due to factors like individual lung microbiological profiles. We aim to investigate Pa response to ETI by integrating phenotypic, transcriptomic, and genomic data to identify adaptive traits and understand variability in treatment outcomes.

Methods

Clonally-related Pa isolates were collected from 3 pwCF before and up to 18 months after starting ETI treatment. Phenotypic traits linked to acute/intermittent infection and chronic colonization were analyzed. Isolates underwent a 6-hour in vitro exposure to ETI or DMSO in artificial sputum medium, simulating the conditions in CF sputum. Bacterial RNA was sequenced, transcripts were quantified, and differential expression (DEA) and pathways enrichment analysis were carried out.

Results

Phenotypic analysis showed strain-dependent adaptation, mainly affecting pyocyanin production and biofilm formation. DEA of longitudinal isolates revealed a small overlap in modulated transcripts across clonal lineages (upregulated=0.3%, downregulated=0.07%), indicating a strain-specific transcriptional response to in vivo ETI exposure. Shared modulated transcripts were linked to secretion systems, beta-lactam resistance, ABC transporters, and metabolic pathways. In vitro ETI treatment caused no consistent transcript modulation across isolates, but 0.6–3.7% of transcripts modulated in vitro were also affected in vivo, suggesting a direct ETI impact. Eight additional pwCF have been recruited, and whole genome sequencing is ongoing to explore pathoadaptive mutations.

Conclusion

Our findings indicate that exposure to ETI treatment can modify specific Pa phenotypic traits and transcriptomes in a pwCF-specific manner, providing insights into variability in treatment efficacy. This study was supported by the Italian CF Foundation (FFC#16/2021).

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来源期刊

Journal of Cystic Fibrosis 医学-呼吸系统

CiteScore

10.10

自引率

13.50%

发文量

1361

审稿时长

50 days

期刊介绍： The Journal of Cystic Fibrosis is the official journal of the European Cystic Fibrosis Society. The journal is devoted to promoting the research and treatment of cystic fibrosis. To this end the journal publishes original scientific articles, editorials, case reports, short communications and other information relevant to cystic fibrosis. The journal also publishes news and articles concerning the activities and policies of the ECFS as well as those of other societies related the ECFS.