Elucidation of the first interspecies chemical signaling mechanisms in Capsaspora owczarzaki--the predator of a human pathogen and a model for the evolution of animal multicellularity

阐明 Capsaspora owczarzaki 中的第一个种间化学信号传导机制——人类病原体的捕食者和动物多细胞进化的模型

• 批准号: 10613475
• 负责人: Joseph P. Gerdt
• 金额: $ 38.93万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613475
• 关键词: Adhesions; Animals; Behavior; Biocontrols; Biomphalaria; Cadherins; Cell Adhesion; Cell Adhesion Process; Cell-Cell Adhesion; Cells; Cellularity; Chemicals; Chemotactic Factors; Chemotaxis; Complex; Cues; Disease; Disseminated Malignant Neoplasm; Environment; Evolution; Exhibits; Genes; Health; Human; Immune; Immune System Diseases; Infection; Integration Host Factors; Integrins; Mission; Modeling; Molecular; Neoplasm Metastasis; Neural Crest Cell; Organism; Phenotype; Phylogenetic Analysis; Reporting; Research; Schistosoma; Schistosomiasis; Serum; Signal Transduction; Snails; United States National Institutes of Health; Work; cancer cell; human pathogen; in vivo evaluation; insight; intercellular communication; migration; neglected tropical diseases; programs; receptor; response; trait; vector transmission

Project Summary / Abstract Capsaspora owczarzaki is a protozoan that may control a neglected tropical disease and reveal the earliest animal cell-cell signaling mechanisms. However, little is known about this organism at a chemical level. Capsas- pora lives inside Biomphalaria snails (the vectors that transmit schistosome worms that cause schistosomiasis). Capsaspora hunts and kills schistosomes, making it a promising biocontrol agent. However, no one knows which molecules Capsaspora senses to colonize its snail host, nor how it senses its schistosome prey. Furthermore, Capsaspora is one of the closest living relatives of animals, with which it shares signaling and adhesion genes. It exhibits reversible aggregation and chemotaxis, reminiscent of human neural crest cells, immune cells, and metastatic cancer cells. Therefore, it is a phylogenetically relevant model to study how multicellular phenotypes in animals evolved and act in healthy and disease states. However, no one has found which molecules regulate Capsaspora’s adhesion and chemotaxis phenotypes to determine if its mechanisms are conserved with those in animals. For Capsaspora to reach its potential as a biocontrol agent and to reveal insight into the evolution of animal multicellularity, its mechanisms of chemical signaling must be uncovered. The proposed research program will discover the molecular mechanisms that regulate two phenotypes, each of which is relevant both to killing schistosomes and to understanding the evolution of multicellular traits in animals. First, Capsaspora forms aggregates in response to snail serum, which is notable for two reasons: (1) it is the only Capsaspora response to a snail host factor, presumably enabling Capsaspora to recognize its snail host environment, and (2) it is the only regulated cell-cell adhesion process in Capsaspora, which is the only non- animal with complete integrin and cadherin adhesion complexes. Therefore, discovery of the mechanism of se- rum-induced aggregation may reveal both how Capsaspora colonizes its host and whether or not regulated animal cellular adhesion mechanisms were active in animals’ common ancestor. Second, Capsaspora migrates toward schistosome prey, which is notable for two reasons: (1) it is the only known avenue by which Capsaspora senses schistosomes, and (2) it is the only reported chemotaxis behavior in the closest relatives of animals (the holozoans). Therefore, discovery of the chemoattractant and response may reveal how Capsaspora hunts schis- tosomes and whether or not animal chemotaxis mechanisms were active in animals’ common ancestor. In both projects, the cue molecule and the Capsaspora receptor will be identified. Subsequent work will decipher how the signal is transduced. Finally, the significance of these phenotypes for snail colonization and schistosome killing will be tested in vivo, and the evolutionary conservation of these signaling mechanisms with present-day animals will be examined. Discovery of the signals and mechanisms that trigger Capsaspora aggregation and chemotaxis may reveal essential traits for Capsaspora to decrease schistosomiasis infections. Furthermore, this work may reveal the most fundamental mechanisms of regulated multicellularity in animals.

项目摘要 /摘要 Capsaspora Owczarzaki是一种原生动物，可以控制被忽视的热带疾病并揭示最早的 动物细胞 - 细胞信号传导机制。但是，对于化学水平上的这种生物知之甚少。辣椒 - Pora生活在生物掌蜗牛内（传播引起血吸虫病的黑斑虫蠕虫的向量）。 Capsaspora狩猎并杀死血吸虫，使其成为有前途的生物防治剂。但是，没人知道哪个 分子囊孢子的感觉使其蜗牛宿主定居，也不是如何感知其血腥猎物的感觉。此外， Capsaspora是动物最接近的生物亲戚之一，它具有信号传导和粘合剂基因。 它表现出可逆的聚集和趋化性，让人联想到人神经rest细胞，免疫细胞和 转移性癌细胞。因此，它是一种研究多细胞表型的系统发育相关模型 在动物中进化并在健康和疾病状态下起作用。但是，没有人发现哪些分子调节 辣椒粉的粘附和趋化表型，以确定其机制是否在 动物。使囊孢子具有生物控制剂的潜力，并揭示了对 动物多细胞性，必须发现其化学信号传导机制。 拟议的研究计划将发现调节两种表型的分子机制，每个表型 这既与杀死血吸虫”以及了解动物中多细胞性状的演变。 首先，辣椒粉形成凝聚力的响应蜗牛血清，这是有两个原因的：（1）它是 只有辣椒孢子对蜗牛宿主因子的反应，大概使Capsaspora能够识别其蜗牛宿主 环境，（2）它是辣椒孢子中唯一受调节的细胞 - 细胞粘合剂过程，这是唯一的非 - 具有完整整联蛋白和钙粘蛋白粘合剂复合物的动物。因此，发现了se的机制 朗姆酒诱导的聚集可能揭示辣椒孢菌如何在其宿主中定居以及是否受调节 动物细胞粘附机制在动物的共同祖先中活跃。其次，辣椒孢子迁移 迈向Schistosome猎物，这是有两个原因的值得注意的：（1）它是唯一已知的顾问大道 感觉血块和（2）它是动物最亲近的亲属中唯一报道的趋化性行为（ Holozoans）。因此，发现趋化剂和反应可能揭示了辣椒孢子如何狩猎schis- tosomes以及动物趋化机制是否活跃在动物的共同祖先中。 在这两个项目中，都将确定提示分子和辣椒粉受体。随后的工作将破译 信号如何翻译。最后，这些表型对蜗牛定殖和血块的意义 杀戮将在体内测试，并使用当今的这些信号传导机制的进化保护 将检查动物。发现触发囊孢子聚集的信号和机制 趋化性可能揭示了囊孢子的基本特征，以减少血吸虫病感染。此外，这个 工作可能揭示了动物受调节多细胞性的最基本机制。