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 卡萨斯孢霉是一种原生动物，它可能控制一种被忽视的热带疾病，并揭示出最早的 动物细胞-细胞信号机制。然而，在化学水平上对这种有机体知之甚少。卡普萨斯- Pora生活在Biomphalaria蜗牛(传播导致血吸虫病的血吸虫的媒介)内。 Capsaspora捕杀血吸虫，使其成为一种很有前途的生防剂。然而，没有人知道是哪一种 Capsaspora的分子感觉到它的蜗牛宿主，也不知道它如何感觉到血吸虫的猎物。此外， 卡萨斯孢菌是现存的动物近亲之一，它与动物具有共同的信号和黏附基因。 它表现出可逆的聚集和趋化作用，使人想起人类神经脊细胞、免疫细胞和 转移性癌细胞。因此，研究多细胞表型是一个系统发育相关的模型。 在健康和疾病状态下进化和行为的动物。然而，还没有人发现哪些分子调节 卡萨斯孢菌的黏附和趋化表型以确定其机制是否与 动物。使Capsaspora发挥其作为生防剂的潜力，并揭示 动物的多细胞特性，其化学信号的机制必须被揭示。 拟议的研究计划将发现调节两种表型的分子机制，每种表型 这既与杀死血吸虫有关，也与了解动物多细胞特征的进化有关。 首先，Capsaspora对蜗牛血清的反应形成聚集体，这一点值得注意的原因有两个：(1)它是 只有Capsaspora对蜗牛宿主因子做出反应，推测使Capsaspora能够识别其蜗牛宿主 (2)这是唯一受调节的细胞-细胞黏附过程，这是唯一的非 具有完整的整合素和钙粘附素黏附复合体的动物。因此，对Se-2作用机理的发现具有重要的现实意义。 朗姆酒诱导的聚集可能揭示卡萨斯孢菌如何定植其宿主以及是否受到调控 动物的细胞黏附机制在动物的共同祖先中是活跃的。第二，卡萨斯波拉的迁徙 对于血吸虫猎物，这一点值得注意，原因有两个：(1)这是卡萨斯孢子虫唯一已知的途径 感觉血吸虫，以及(2)这是唯一报道的动物近亲的趋化性行为( 全息虫)。因此，化学诱导剂和反应的发现可能揭示卡萨斯孢霉是如何捕杀裂殖吸虫的。 染色体和动物趋化机制在动物的共同祖先中是否活跃。 在这两个项目中，都将识别线索分子和Capsaspora受体。后续工作将破译 信号是如何传递的。最后，这些表型对钉螺定植和血吸虫的意义。 杀戮将在体内进行测试，这些信号机制的进化保守与当今 动物将接受检查。发现触发Capsaspora聚集性和 趋化性可能揭示了卡萨斯孢子虫减少血吸虫病感染的基本特征。此外，这一点 这项工作可能会揭示动物体内受调控的多细胞的最基本机制。