动物宿主与多种寄生生物相互作用的代谢组学分析

寄生生物包括寄生虫、细菌和病毒。多种寄生生物的共感染是普遍现象，多寄生生物之间以及与宿主之间必然产生相互作用。研究宿主与多种寄生生物的相互作用是发展感染早期诊断的基础，是需要解决的重大科学问题。目前，寄生生物共染的研究主要集中在免疫学方面，也取得了一定的进展。但是，这些研究对宿主与多寄生生物的相互作用的分子表型和代谢机制尚无全面系统的认识。本项目拟以代谢组学为主要研究手段，在系统层面上揭示宿主与多种病原体相互作用的代谢表型这一关键科学问题。为此，我们将首先整合基于磁共振和质谱的代谢组学检测方法，实现对极性代谢物快速灵敏的结构确定。然后以小鼠为模型研究宿主被血吸虫-沙门氏菌共感染后代谢组的变化，并结合免疫学手段系统地分析多种病原体单独和共感染后不同时程的代谢组变化，以揭示宿主与多病原体相互作用的分子表型和代谢机制，为研究其它多寄生生物与宿主的相互作用提供研究手段。

Infectious diseases, such as tuberculosis, AIDS, schistosomiasis and hepatitis, are endemic in China, brought heavy burden to public health and economic growth. They are caused by infecting human or animal hosts with corresponding pathogens, such as Mycobacterim tuberculosis, HIV virus and parasites etc. The underline factors contributing to the current endemic situation are lacking of effective immunization against the infection, early diagnostic methods and effective treatments. The problem becomes worse and more complicated by presence of multiple infective organisms, which is common phenomenon in clinics. Understanding the interaction between hosts and pathogens can provide important information for discovering diagnostic biomarkers and for designing effective new drugs. Metabolomics is a newly emerging analytical technique, which combines multivariate data analysis method with metabolic profiles generated from nuclear magnetic resonance (NMR) or mass spectrometry (MS). Since the birth of the technique, it has been applied to many research fields, such as the study of disease processes, drug toxicity, and interactions between animal hosts and parasites. The key tasks for metabonomic technique are to uncover metabonome information both quantitively and qualitively. Currently the structure elucidation of polar molecules from complex mixtures, such as urine and plasma is still a bottleneck. Therefore, in the current investigation, we will first of all aim to develop a fast, effective tool for structure elucidation of polar molecules from complex mixtures and then employ the developed metabonomic technique to investigate the interactions between animal host and infective organisms. To complete the tasks, we will design and prepare columns enabling separation and enrichment of polar metabolites and followed by incorporating the prepared columns into our existing hyphenated system (HPLC-SPE-CryoNMR-MS) and to finally achieve a fast, effective structure elucidation method. We will subsequently integrate NMR and MS metabolic profiling techniques to enhance sensitivity and structure elucidation power. We then apply the newly developed technique to investigate metabolic interactions between mice and Salmonella, and interactions between mice and multiple organisms, such as, schistosome- Salmonella. The altered metabolic pathways corresponding to single and double infections will subsequently be elucidated. Finally, these altered metabolic pathways will be further investigated using immuno assays. Summarization of the proposed project could generate metabolic mechanisms between hosts, providing important information for designing new sensitive drugs and could also shed some light on diagnosis of early infections in clinical settings.