Molecular negotiations at the host-parasite interface

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。对于大型后生寄生虫，如线虫，尤其如此，它们会感染胃肠道和内部组织。宿主可以抵抗几乎所有寄生虫的感染，而且宿主与寄生虫的相互作用通常是非常特异性的。线虫寄生的这个基本方面是如何在分子水平上决定的仍然是一个谜。我们的驱动假设是，寄生线虫分泌的分子选择性地和特异性地调节宿主的免疫反应，通常会防止感染。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。这些相互作用对容许宿主是特异性的，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，并阐明寄生的进化过程。寄生线虫分泌外泌体，这是一种将分子信息传递给细胞的小泡。外泌体运送蛋白质、mrna和microrna （mirna）作为其货物的一部分。对于组织寄生丝虫病，在感染期间，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宿主免疫细胞的功能。这些制剂包括多种寄生虫mirna，我们已经使用生物信息学分析来鉴定其中几种候选宿主免疫反应基因靶点。***我们将鉴定作用于树突状细胞的寄生虫mirna，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或其靶mRNA识别种子序列的单个核苷酸变化可显著改变其作用。6-8个核苷酸种子区必须与目标mRNA完全匹配。mrna这一区域的核苷酸序列在不同物种之间通常是可变的；我们已经确定了在宿主免疫途径中具有高质量mRNA靶点的寄生虫mirna，这些靶点是物种特异性的。利用生物信息学、树突状细胞功能分析和qPCR，我们将表征这些寄生虫mirna的物种特异性。我们将对六种寄生线虫选择性感染三种哺乳动物宿主的mirna进行表征，以确定这些分子是否作用于免疫反应途径，这些途径在系统发育上不同的病原体中是趋同进化的目标，但这些寄生虫的感染仅限于它们的允许宿主

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.**