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.

项目摘要/摘要 尽管宿主免疫系统高度活跃，但血液中的血液中有敌对的环境，但是 寄生虫引起血吸虫病影响全球超过2亿个人的血吸虫病，具有 几十年来，在脉管系统中繁衍生息的出色能力。团队（外皮）有 我们被证明在寄生虫免疫逃避中起着重要作用，仍然是神秘的是一种机制 寄生虫中和从宿主血液中摄取的大量免疫成分。我们的 最近发表的工作表明，食管腺，寄生虫消化的抗牙科器官 区域对于血块在血液中生存至关重要。它通过裂解摄入的免疫细胞运行 在将它们传递到肠道中之前，阻止它们进入内部寄生虫组织。这样的观察 导致我们假设特定的食管腺蛋白阻滞和/或降解宿主免疫成分， 从而确保寄生虫生存。我们感兴趣的主要问题是： 降解和/或阻断宿主免疫成分的食管腺因子以及这种功能如何 有助于寄生虫生存？寄生虫免疫中特定食管因子的机理是什么 逃避？这些将以三个特定目的进行研究：1）定义食管腺细胞类型和 基因； 2）确定特定食管因子在免疫细胞裂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因子因子的机制。在第一个目标中 我们将通过与寄生虫之间的RNA-seq数据进行比较和 没有食管腺组织。在第二个目标中，我们将在功能上质疑已识别的基因 RNAi与体外进食测定法相结合，并确定候选基因缺陷寄生虫的生存能力 在哺乳动物主持人内部。这些目的的初步结果揭示了数十个食管腺因子，两个因素 其中似乎对于降解宿主免疫细胞至关重要。在第三个目标中，我们将确定 两种候选蛋白的活性，识别其结合伴侣，并破译宿主寄生虫的机制 相互作用。我们共同希望将新见解带入Schistosomes的食管腺介导的免疫 通过识别基本的食管腺因子及其作用方式来逃避机制。提议 研究具有创新性，因为我们的发现可能会改变血吸虫免疫进化的范式，这具有 人们认为我们主要是由它的tegument驱动的。我们的研究很重要，因为它桥接了寄生虫 通过识别基本的食管分子并理解发育和翻译生物学 他们的运作方式。将来可能会探索这些候选人作为潜在的治疗目标 补充praziquantel的局限性，并共同促进了针对血吸虫病的斗争。