Investigations of Parasite-Host-Microbiota Interactions Using Cutting-edge Genomics and bioinformatics technologies

发达国家过敏性和自身免疫性疾病发病率的增加归因于儿童接触病原体的减少，这些病原体对无害的刺激造成不适当的免疫反应。因此，有人试图利用这一“卫生假说”，将其中一些感染性病原体，特别是肠道蠕虫，重新引入患者体内，作为新的免疫疗法。然而，蠕虫调节免疫系统的确切机制尚不清楚。最近的研究建立了胃肠道寄生虫感染与肠道微生物区系组成和选定微生物物种相对丰度的变化之间的联系，从而促使人们提出假设，胃肠道寄生虫调节脊椎动物宿主免疫反应的能力可能在一定程度上与共生组成的变化有关。然而，到目前为止，关于寄生蠕虫、脊椎动物宿主及其共生微生物群之间的相互作用的数据缺乏。阐明寄生虫、宿主和肠道微生物区系之间的复杂关系是至关重要的，因为越来越需要一种综合的方法来了解宿主-病原体的相互作用，这反过来又为将实验结果转化为临床奠定了基础。最近的技术进步为研究这些相互作用的各个方面提供了独特的机会。例如，高通量测序平台与生物信息学技术相结合，能够及时处理大量序列输出，从而能够识别与寄生虫在其最终宿主的胃肠道中建立相关的宿主基因和微生物种群和/或物种。该项目的具体研究目标将是：(1)确定蠕虫诱导的脊椎动物宿主实验感染后肠道微生物区系的变化；(2)利用下一代测序技术和生物信息学分析寄生虫感染后的转录调控；(3)确定肠道微生物区系在寄生虫介导的抑制炎症中的作用以及蠕虫诱导的宿主基因表达调控的相对贡献；(4)为开发基于蠕虫的肠道炎症疾病的新疗法选择候选细菌物种。这一跨学科项目将整合寄生虫学、微生物学、免疫学、遗传学、分子生物学和生物信息学的关键领域，并提供这些领域的基本技能。这个项目是及时的，因为它的结果不仅将对未来寄生虫的生物学和起源本身的研究产生广泛的影响，而且还将为旨在利用寄生虫的免疫逃避策略开发基于蠕虫的慢性炎症性疾病疗法的研究铺平道路。

The increased incidence of allergic and autoimmune disorders in developed countries has been attributed to a decline in childhood exposure to pathogens that causes inappropriate immune responses to harmless stimuli. Thus, several attempts have been made to exploit this 'hygiene hypothesis' by reintroducing some of these infectious agents, particularly intestinal worms, into patients as novel immunotherapy. However, the precise mechanisms by which worms modulate the immune system are unclear. Recent studies have established a link between infections by gastrointestinal parasitic helminths and modifications of the composition of the gut microbiota and relative abundance of selected microbial species, thus prompting the hypothesis that the ability of gastrointestinal parasites to modulate the immune response of the vertebrate hosts may be in part associated to changes in the commensal makeup. However, thus far, data on the interactions between parasitic helminths, vertebrate hosts and their commensal microbiota is lacking. Elucidating the complex relationships between the parasite, the host and the gut microbiota is crucial, because of an increasing need for an integrated approach to understand host---pathogen interactions that, in turn, underpin the translation of experimental findings to the clinic. Recent technological advances provide unique opportunities to investigate various aspects of these interactions. For instance, high---throughput sequencing platforms, together with bioinformatics techniques that allow timely processing of large sequence outputs, enable the identification of host genes and microbial populations and/or species associated with the establishment of a parasite in the gastrointestinal tract of its definitive host. The specific research aims of this project will be: (1) to determine helminth---induced changes in gut microbiota following experimental infection of vertebrate hosts; (2) to conduct analyses of transcriptional regulation following parasite infection using next---generation sequencing technologies and bioinformatics; (3) to establish the role of the gut microbiota and the relative contribution of helminth---induced modulation of host gene expression in parasite---mediated suppression of inflammation; (4) to select candidate bacterial species for the development of novel helminth---based therapies of gut inflammatory disorders. This interdisciplinary project will integrate key areas of parasitology, microbiology, immunology, genetics, molecular biology and bioinformatics and will provide essential skills in these areas. This project is timely, since its outcomes will not only have broad implications for future studies of the biology and origin of parasitism itself, but will also pave the way to investigations aimed at exploiting the immunoevasive strategies of parasites for the development of helminth---based therapeutics for chronic inflammatory disorders.