双物种蛋白质组学与动物-病原体相互作用的靶向干预。

Yang Sylvia Liu, Chengqian Zhang, Bee Luan Khoo, Piliang Hao, Song Lin Chua
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引用次数: 0

摘要

引言:宿主与微生物之间的相互作用对人类健康和全球生态系统都非常重要,因此阐明复杂的宿主与微生物之间的相互作用以及相关的蛋白质表达需要开发灵敏、准确的生化技术。目前的蛋白质组学技术可以从宿主或微生物的角度揭示信息,但不能提供相应伙伴的数据。此外,同时研究反映宿主与微生物之间直接竞争的宿主-微生物蛋白质组仍然具有挑战性。这就需要为宿主与微生物的相互作用开发一种双物种蛋白质组学方法:我们旨在建立一种正向+反向的细胞培养氨基酸稳定同位素标记(SILAC)蛋白质组学方法,在不进行物理隔离的情况下同时标记和量化宿主和微生物新表达的蛋白质,以研究宿主与微生物直接相互作用的机制:方法:我们利用秀丽隐杆线虫-铜绿假单胞菌感染模型作为概念验证,采用SILAC蛋白质组学和分子通路分析来描述微生物和宿主的差异表达蛋白质。然后,我们利用分子对接和化学特性鉴定出了能阻断宿主-微生物相互作用并消除微生物感染的化学抑制剂:根据蛋白质组学的结果,我们研究了病原体铁清除蛋白与宿主铁吸收蛋白之间的铁竞争,其中铜绿微囊藻上调了吡佛尔定合成蛋白(PvdA)(折叠变化为 5.2313)并分泌吡佛尔定,而秀丽隐杆线虫表达了铁蛋白(FTN-2)(折叠变化为 3.4057)。高良姜素是一种源自生姜的植物化学物质,可抑制铜绿微囊藻产生吡咯韦啶和形成生物膜,从而实现对铁竞争的靶向干预。高良姜素-环丙沙星联合疗法可以消除鱼类伤口感染模型中的铜绿假单胞菌生物膜,并使动物存活:我们的工作提供了一种基于 SILAC 的新型蛋白质组学方法,可同时评估宿主和微生物蛋白质组,未来可应用于高等宿主生物和其他微生物物种。结论:我们的工作提供了一种新颖的基于 SILAC 的蛋白质组学方法,可同时评估宿主和微生物蛋白质组,未来可应用于高等宿主生物和其他微生物物种。
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Dual-species proteomics and targeted intervention of animal-pathogen interactions.

Introduction: Host-microbe interactions are important to human health and ecosystems globally, so elucidating the complex host-microbe interactions and associated protein expressions drives the need to develop sensitive and accurate biochemical techniques. Current proteomics techniques reveal information from the point of view of either the host or microbe, but do not provide data on the corresponding partner. Moreover, it remains challenging to simultaneously study host-microbe proteomes that reflect the direct competition between host and microbe. This raises the need to develop a dual-species proteomics method for host-microbe interactions.

Objectives: We aim to establish a forward + reverse Stable Isotope Labeling with Amino acids in Cell culture (SILAC) proteomics approach to simultaneously label and quantify newly-expressed proteins of host and microbe without physical isolation, for investigating mechanisms in direct host-microbe interactions.

Methods: Using Caenorhabditis elegans-Pseudomonas aeruginosa infection model as proof-of-concept, we employed SILAC proteomics and molecular pathway analysis to characterize the differentially-expressed microbial and host proteins. We then used molecular docking and chemical characterization to identify chemical inhibitors that intercept host-microbe interactions and eliminate microbial infection.

Results: Based on our proteomics results, we studied the iron competition between pathogen iron scavenger and host iron uptake protein, where P. aeruginosa upregulated pyoverdine synthesis protein (PvdA) (fold-change of 5.2313) and secreted pyoverdine, and C. elegans expressed ferritin (FTN-2) (fold-change of 3.4057). Targeted intervention of iron competition was achieved using Galangin, a ginger-derived phytochemical that inhibited pyoverdine production and biofilm formation in P. aeruginosa. The Galangin-ciprofloxacin combinatorial therapy could eliminate P. aeruginosa biofilms in a fish wound infection model, and enabled animal survival.

Conclusion: Our work provides a novel SILAC-based proteomics method that can simultaneously evaluate host and microbe proteomes, with future applications in higher host organisms and other microbial species. It also provides insights into the mechanisms dictating host-microbe interactions, offering novel strategies for anti-infective therapy.

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