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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=709362
• 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.

感染的成功或失败取决于宿主和病原体之间分子对话的结果。对于感染胃肠道和内部组织的大型后生动物寄生虫（例如线虫）尤其如此。宿主可以抵抗几乎所有寄生虫种类的感染，并且宿主与寄生虫的相互作用通常是非常特定的。如何在分子水平上确定线虫寄生的这一基本方面仍然是个谜。我们的驱动假设是，寄生线虫分泌的分子选择性地、特异性地调节宿主免疫反应，这些反应通常可以预防感染。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。这些相互作用对于允许的宿主是特异性的，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，并阐明寄生所涉及的进化过程。 寄生线虫分泌外泌体，即向细胞传递分子信息的小囊泡。外泌体输送蛋白质、mRNA 和 microRNA (miRNA) 作为其货物的一部分。对于组织内丝虫来说，感染期间宿主血液中会出现数百种寄生虫 miRNA。线虫 miRNA 抑制基因表达并影响培养物中宿主免疫细胞的功能。这些制剂包括多种寄生虫 miRNA，我们使用生物信息学分析来识别其中几种的候选宿主免疫反应基因靶标。 我们将鉴定作用于树突状细胞（免疫反应的关键调节因子）的寄生虫 miRNA。我们的首要任务是识别那些以宿主物种特异性方式起作用的 miRNA，从而可能在宿主-寄生虫特异性的进化中发挥作用。 miRNA 或其 mRNA 靶标的识别种子序列中的单个核苷酸变化可以显着改变它们的效果。 6-8 个核苷酸的种子区域必须与目标 mRNA 完美匹配。该 mRNA 区域的核苷酸序列通常在不同物种之间存在差异；我们已经鉴定出寄生虫 miRNA，它们在宿主免疫途径中具有物种特异性的高质量 mRNA 靶标。利用生物信息学、树突状细胞功能测定和 qPCR，我们将表征这些寄生虫 miRNA 的物种特异性。我们将表征来自六种寄生线虫的 miRNA，选择性感染三种哺乳动物宿主，以确定这些分子是否作用于系统发育不同病原体之间趋同进化的目标免疫反应途径，但将这些寄生虫的感染仅限于其允许的宿主。