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

人类寄生虫曼氏血吸虫食管腺介导的免疫逃避

• 批准号: 10797534
• 负责人: Jayhun Lee
• 金额: $ 39.77万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-24 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10797534
• 关键词: Affect; Anterior; Atlases; Binding; Biological Assay; Biology; Blood; Blood Circulation; Candidate Disease Gene; Cells; Cessation of life; Complement; Coupled; Cytolysis; Cytoplasm; Data; Development; Endowment; Ensure; Environment; Esophagus; Exons; Future; Gastrointestinal tract structure; Genes; Gland; Goals; Heterogeneity; Homeostasis; Human; Immune; Immune Evasion; Immune system; Immunocompromised Host; Immunoglobulins; In Situ Hybridization; In Vitro; Individual; Ingestion; Leukocytes; Link; Maintenance; Mass Spectrum Analysis; Mediating; Molecular; Mus; Organ; Parasites; Penetration; Physiologic pulse; Platyhelminths; Play; Praziquantel; Proteins; Public Health; Publishing; RNA Interference; Research; Role; Schistosoma; Schistosoma mansoni; Schistosomiasis; Site; Skin; Therapeutic; Tissue atlas; Tissues; Transplantation; Vaccines; Work; cell type; chemotherapy; comparative; design; esophageal gland; feeding; fighting; forkhead protein; human pathogen; in vivo; innovation; insight; interest; knock-down; new therapeutic target; novel; prevent; protein function; stem cells; therapeutic target; transcriptome sequencing; transcriptomics

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.

项目概要/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影响了全球 2 亿多人， 其在脉管系统内存活数十年的卓越能力，而皮膜（外层皮肤）却具有这种能力。 已被证明在寄生虫免疫逃避中发挥重要作用，但其机制仍然是个谜 这些寄生虫会中和从宿主血液中摄取的大量免疫成分。 最近发表的研究表明，食管腺是寄生虫消化系统的前部附属器官。 道，对于血吸虫在血液中生存至关重要，它通过裂解摄入的免疫细胞来发挥作用。 在将它们传递到肠道之前，防止它们进入内部寄生虫组织。 引导我们捕获特定的食管腺蛋白阻断和/或降解宿主免疫成分， 确保寄生虫的生存我们感兴趣的主要问题是：其作用是什么。 食管腺降解和/或阻断宿主免疫成分的因素以及这些功能如何发挥作用 有助于寄生虫存活的特定食管腺因子在寄生虫免疫中的机制是什么？ 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和 2) 确定特定食管腺因子在免疫细胞裂解和寄生虫存活中的作用； 3）确定宿主-寄生虫相互作用中特定食管腺因子的机制。 我们将通过比较寄生虫之间的RNA-seq数据来系统地识别食管腺基因 在没有食管腺组织的情况下，我们将使用功能性地询问已识别的基因。 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 这些目标的初步结果揭示了数十种食管腺因素，其中两种。 其中似乎对于降解宿主免疫细胞至关重要。因此，在第三个目标中，我们将确定 两种候选蛋白的活性，识别它们的结合伙伴，并破译宿主-寄生虫的机制 我们期望共同为血吸虫食管腺介导的免疫带来新的见解。 通过识别重要的食管腺因子及其作用方式来确定逃避机制。 这项研究具有创新性，因为我们的研究结果可能会改变血吸虫免疫逃避的范式，这已经 我们的研究被认为主要是由其外皮驱动的，因为它桥接了寄生虫。 通过识别重要的食管腺分子并理解发育和转化生物学 这些候选者可能在未来被用作潜在的治疗靶点。 吡喹酮的补充和限制共同有助于抗击血吸虫病。