Molecular negotiations at the host-parasite interface

宿主-寄生虫界面的分子谈判

• 批准号: RGPIN-2016-06602
• 负责人: Geary, Timothy
• 金额: $ 3.93万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=690461
• 关键词: Molecular; negotiations; host; parasite; interface

The success or failure of an infection depends on the outcome of a molecular dialog between host and pathogen. This is especially true for large metazoan parasites such as nematodes, which infect the gastrointestinal tract and internal tissues. Hosts resist infection by almost all parasite species, and host-parasite interactions are typically quite specific. How this fundamental aspect of nematode parasitism is determined at the molecular level remains a mystery. Our driving hypothesis is that molecules secreted by parasitic nematodes selectively and specifically modulate host immune responses that would normally prevent infection. Parasite molecules interact with host immune cells at the receptor level and at the level of gene regulation. These interactions are specific for permissive hosts and establish the molecular basis of host-parasite specificity. Understanding the molecules used by parasites to accomplish this immunomodulation will reveal the molecular basis for host-parasite specificity and illuminate the evolutionary processes involved in parasitism.***Parasitic nematodes secrete exosomes, small vesicles that deliver molecular information to cells. Exosomes deliver proteins, mRNAs and microRNAs (miRNAs) as part of their cargo. For tissue-dwelling filariae, hundreds of parasite miRNAs appear in host blood during an infection. Nematode miRNAs repress gene expression and affect the function of host immune cells in culture. These preparations include multiple parasite miRNAs, and we have used bioinformatics analyses to identify candidate host immune response gene targets for several of them.***We will identify parasite miRNAs that act on dendritic cells, key regulators of immune responses. Our top priority is to identify those miRNAs that act in a host species-specific manner and thus may play a role in the evolution of host-parasite specificity. A single nucleotide change in the recognition seed sequence of miRNAs or their mRNA target can dramatically alter their effects. The 6-8 nucleotide seed region must match perfectly to the target mRNA. Nucleotide sequences in this region of mRNAs are typically variable across species; we have identified parasite miRNAs that have high-quality mRNA targets in host immune pathways that are species-specific. Using bioinformatics, dendritic cell functional assays and qPCR, we will characterize the species specificity of these parasite miRNAs. We will characterize miRNAs from six species of parasitic nematodes to that selectively infect three mammalian hosts to determine if these molecules act on immune response pathways that are targeted by convergent evolution among phylogenetically distinct pathogens, but that restrict infection by these parasites only to their permissive hosts.**

感染的成败取决于宿主和病原体之间分子对话的结果。对于大型后生动物寄生虫来说尤其如此，例如线虫，它们感染胃肠道和内部组织。宿主抵抗几乎所有寄生虫物种的感染，宿主与寄生虫的相互作用通常是非常特异的。线虫寄生的这一基本方面是如何在分子水平上确定的，仍然是一个谜。我们的驱动假设是，寄生线虫分泌的分子选择性和特异性地调节通常可以防止感染的宿主免疫反应。寄生虫分子在受体水平和基因调控水平上与宿主免疫细胞相互作用。这些相互作用是允许宿主特有的，并建立了宿主-寄生虫特异性的分子基础。了解寄生虫用来完成这种免疫调节的分子将揭示宿主-寄生虫特异性的分子基础，并阐明涉及寄生的进化过程。*寄生线虫分泌外体，即向细胞传递分子信息的小囊泡。外切体将蛋白质、mRNAs和microRNAs(MiRNAs)作为其货物的一部分进行运输。对于组织寄居的丝虫，在感染期间，宿主血液中会出现数百种寄生虫miRNAs。线虫miRNAs在培养中抑制基因表达，影响宿主免疫细胞的功能。这些准备包括多个寄生虫miRNAs，我们使用生物信息学分析来确定其中几个的候选宿主免疫反应基因靶点。*我们将识别作用于树突状细胞的寄生虫miRNAs，树突状细胞是免疫反应的关键调节因子。我们的首要任务是确定那些以宿主物种特有的方式发挥作用的miRNAs，从而可能在宿主-寄生虫特异性的进化中发挥作用。MiRNAs或其信使核糖核酸靶标的识别种子序列中的单个核苷酸变化就能极大地改变它们的效果。6-8个核苷酸的种子区必须与目标mRNA完全匹配。这一mRNAs区域的核苷酸序列在不同物种之间通常是不同的；我们已经识别出寄生虫miRNAs在宿主免疫途径中具有高质量的mRNAs靶标，这是物种特有的。利用生物信息学、树突状细胞功能分析和定量聚合酶链式反应，我们将鉴定这些寄生虫miRNAs的物种特异性。我们将对来自六种寄生线虫的miRNAs进行特征描述，这些miRNAs选择性地感染三种哺乳动物宿主，以确定这些分子是否作用于免疫反应途径，这些免疫反应途径是系统发育上不同的病原体之间的趋同进化所针对的，但限制了这些寄生虫仅感染它们允许的宿主。