Esophageal gland-mediated immune evasion by the human parasite Schistosoma mansoni

项目总结/摘要 尽管宿主免疫系统高度活跃的血流环境恶劣， 寄生扁虫会导致血吸虫病，影响全球2亿多人，它们具有 几十年来在脉管系统中茁壮成长的非凡能力。虽然皮层（外层皮肤） 虽然已经证明在寄生虫免疫逃避中起重要作用，但仍然是一个谜的是， 这些寄生虫中和了它们从宿主血液中摄取的大量免疫成分。我们 最近发表的工作表明，食道腺，寄生虫消化的前附属器官， 在血液循环系统中，它是染色体在血液中生存所必需的。它通过溶解摄入的免疫细胞 在进入肠道之前，防止它们进入内部寄生虫组织。这种观测 使我们假设特异性食管腺蛋白阻断和/或降解宿主免疫组分， 从而确保寄生虫存活。我们感兴趣的主要问题是： 食管腺因子在降解和/或阻断宿主免疫组分中的作用以及这些功能是如何发挥的 有助于寄生虫的生存特异性食管腺因子在寄生虫免疫中的作用机制是什么 逃避？这些将在三个具体目标下进行研究：1）定义食管腺细胞类型， 2）确定特异性食管腺因子在免疫细胞溶解和寄生虫存活中的作用;和 3)确定宿主-寄生虫相互作用中特定食管腺因子的机制。在第一个目标中， 我们将通过比较寄生虫与和寄生虫之间的RNA-seq数据， 没有食道腺组织在第二个目标中，我们将使用 RNAi与体外饲养试验相结合，并确定候选基因缺陷寄生虫的生存能力 在哺乳动物宿主体内这些目标的初步结果揭示了几十个食管腺因素，两个 其中似乎是降解宿主免疫细胞所必需的。因此，在第三个目标中，我们将确定 两个候选蛋白的活性，鉴定它们的结合伴侣，并破译宿主-寄生虫的机制 互动总之，我们期望为Escherosomes的食管腺介导的免疫功能带来新的见解。 通过识别必需的食管腺因子及其作用模式来研究逃避机制。拟议 这项研究是创新的，因为我们的发现可能会改变令人讨厌的免疫逃避的范式， 被认为主要是由它的皮层驱动的。我们的研究意义重大，因为它连接了寄生虫 通过识别必需的食管腺分子和理解 他们如何运作。这些候选物将来可能被开发为潜在的治疗靶点， 补充吡喹酮的局限性，共同为防治血吸虫病作出贡献。

PROJECT SUMMARY/ABSTRACT Despite the hostile environment of the bloodstream where the host immune system is highly active, schistosomes, parasitic flatworms that cause schistosomiasis that affects over 200 million individuals globally, have a remarkable ability to thrive inside the vasculature for over several decades. While the tegument (outer skin) has been shown to play an important role in parasite immune evasion, what remains a mystery is the mechanism by which parasites neutralize large amounts of immune components that they ingest from the host blood. Our recently published work reveals that the esophageal gland, an anterior accessory organ of parasite’s digestive tract, is essential for schistosomes to survive inside the bloodstream. It operates by lysing ingested immune cells before passing them into the gut, preventing them from accessing the inner parasite tissues. Such observations lead us to hypothesize that specific esophageal gland proteins block and/or degrade host immune components, thereby ensuring parasite survival. The main questions that we are interested in are: What are the roles of esophageal gland factors in degrading and/or blocking host immune components and how do such functions contribute to parasite survival? What is the mechanism of specific esophageal gland factors in parasite immune evasion? These will be investigated under three specific aims: 1) Define the esophageal gland cell types and genes; 2) Determine the role of specific esophageal gland factors in immune cell lysis and parasite survival; and 3) Determine the mechanism of specific esophageal gland factors in host-parasite interaction. In the first aim, we will systematically identify esophageal gland genes by comparing RNA-seq data between parasites with and without the esophageal gland tissue. In the second aim, we will functionally interrogate identified genes using RNAi coupled with an in vitro feeding assay, and determine the viability of candidate gene-deficient parasites inside the mammalian host. Preliminary results from these aims reveal dozens of esophageal gland factors, two of which appear to be essential for degrading host immune cells. Thus, in the third aim, we will determine the activity of the two candidate proteins, identify their binding partners, and decipher the mechanism of host-parasite interaction. Together, we expect to bring new insights to schistosomes’ esophageal gland-mediated immune evasion mechanism by identifying essential esophageal gland factors and their mode of action. The proposed study is innovative since our findings will likely shift the paradigm of schistosome immune evasion, which has been thought to be driven primarily by its tegument. Our study is significant since it bridges parasite developmental and translational biology by identifying essential esophageal gland molecules and understanding how they operate. These candidates may be exploited in the future as potential therapeutic targets that can complement praziquantel in its limitations and collectively contribute to the fight against schistosomiasis.