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

项目摘要/摘要 尽管血液环境恶劣，宿主免疫系统高度活跃，但血吸虫， 引起血吸虫病的寄生扁虫在全球范围内影响着超过2亿人，它们有一种 在血管系统内茁壮成长几十年的非凡能力。而被膜(外皮)则有 已被证明在寄生虫免疫逃避中发挥重要作用，但仍然是一个谜，其机制是 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。我们的 最近发表的研究表明，食管腺是寄生虫消化的前附属器官。 肠道是血吸虫在血液中生存所必需的。它通过裂解摄入的免疫细胞来运作 在它们进入肠道之前，防止它们进入内部寄生虫组织。这样的观察结果 这让我们假设，特定的食管腺蛋白可以阻断和/或降解宿主免疫成分， 从而确保寄生虫的存活。我们感兴趣的主要问题是： 食管腺因子在降解和/或阻断宿主免疫成分中的作用及其功能 对寄生虫的生存有贡献吗？食管腺特异性因子在寄生虫免疫中的作用机制 逃避？这些将在三个具体目标下进行调查：1)确定食管腺细胞类型和 基因；2)确定特定食管腺因子在免疫细胞溶解和寄生虫生存中的作用；以及 3)确定特定食管腺因子在宿主-寄生虫相互作用中的作用机制。第一个目标是， 我们将通过比较寄生虫和寄生虫之间的rna-seq数据来系统地识别食管腺基因。 没有食管腺组织。在第二个目标中，我们将使用以下工具从功能上询问已识别的基因 RNAi与体外喂养试验相结合，并确定候选基因缺陷寄生虫的生存能力 在哺乳动物的宿主体内。这些目标的初步结果揭示了数十种食管腺因素，两种 其中似乎对降解宿主免疫细胞是必不可少的。因此，在第三个目标中，我们将确定 这两个候选蛋白的活性，确定它们的结合伙伴，并破译宿主-寄生虫的机制 互动。我们希望共同为血吸虫食管腺介导的免疫带来新的见解 通过确定食管腺关键因子及其作用方式的逃避机制。建议数 这项研究是创新的，因为我们的发现可能会改变血吸虫免疫逃避的范式，这已经 被认为主要是由它的覆盖层驱动的。我们的研究很有意义，因为它连接了寄生虫 通过识别必要的食管腺分子和理解发育和翻译生物学 他们是如何运作的。这些候选对象未来可能被开发为潜在的治疗靶点，可以 补充吡喹酮的局限性，共同为抗击血吸虫病做出贡献。

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.