Characterizing sexual development of the human parasite Schistosoma mansoni

人类寄生虫曼氏血吸虫的性发育特征

• 批准号: 10441417
• 负责人: James J Collins
• 金额: $ 59.76万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441417
• 关键词: Address; Affect; Behavior; Blood Vessels; Cells; Coupling; Cues; Data; Development; Developmental Biology; Disease; Essential Genes; Event; Female; Formulation; GLI gene; Gene Expression; Genes; Genetic Transcription; Human; In Vitro; Maintenance; Mediating; Modernization; Molecular; Muscle; Muscle Cells; Nature; Nervous system structure; Neurons; Oocytes; Parasites; Parasitology; Pathology; Persons; Platyhelminths; Positioning Attribute; Process; Production; Public Health; RNA Interference; RNA interference screen; Reproduction; Reproductive system; Research; Schistosoma; Schistosoma mansoni; Schistosomiasis; Sexual Development; Sexual Maturation; Signal Transduction; Somatic Cell; Stimulus; Testing; Tissues; adverse outcome; base; cell type; combat; egg; gene discovery; germline stem cells; human old age (65+); human pathogen; insight; male; neglected tropical diseases; new therapeutic target; novel; novel therapeutics; organ growth; reproductive; reproductive development; reproductive organ; response; single-cell RNA sequencing; stem; tool; transcription factor

Schistosomiasis is a neglected tropical disease caused by parasitic flatworms, called schistosomes, that affects hundreds of millions of the world’s poorest people. The pathology of this disease stems from the fact that schistosomes can lay hundreds-to-thousands of eggs per day while living in the blood vessels of their human hosts. Therefore, understanding the mechanisms that control schistosome egg production could present new opportunities to both limit the spread of the disease and abrogate the pathology caused by the parasite. Interestingly, female schistosomes only become sexually mature when they are in constant physical contact with a male worm. Indeed, females grown in the absence of male worms produce no eggs and cause no serious adverse consequences in their hosts. Although the requirement of male worms for female sexual development was described almost 100 years ago, there are few insights into how this process is regulated on a molecular level. A major impediment for addressing this issue is that current culture conditions do not support schistosome sexual development in vitro. To address this issue we have developed a novel media formulation that supports male-induced female sexual development and long-term egg production in vitro. Capitalizing on this medium, we have made two important observations. First, we find that gene expression changes in females immediately upon pairing with a male worm do not occur in the reproductive organs, but rather in the parasite’s somatic tissues including neurons and muscle cells. Second, we identified a transcription factor highly expressed in the nervous system and muscle cells that is essential for female sexual development after pairing with a male worm. Based on these data, we hypothesize that somatic non-reproductive cell types in the female worm are responsible for perceiving the presence of the male worm and in turn regulating the development of the reproductive organs. Defining the cell types directly responsible for perceiving the presence of the male worm could provide important clues about the nature of the male-derived signal that controls female sexual development. Therefore, we will test our central hypothesis in two specific aims. In Specific Aim 1 we will describe the cellular and molecular response of the reproductive and somatic tissues of the female worm to pairing with a male worm using basic developmental biology approaches and single cell RNA sequencing. Specific Aim 2 will utilize RNA interference and single cell RNA sequencing to discover genes and somatic cell types that are essential for controlling female maturation and determine how these genes act in concert to coordinate the female response to pairing with a male. We expect these studies to define the signaling events that stimulate female maturation and hope they will suggest new therapeutic targets against schistosomes.

血吸虫病是一种被忽视的热带疾病，由寄生扁虫（称为血吸虫）引起， 这影响到世界上数亿最贫穷的人。这种疾病的病理源于 因为血吸虫生活在水中，每天可以产下数百至数千个卵。 人类宿主的血管。因此，了解控制机制 血吸虫卵的产生可能为限制该疾病的传播提供新的机会 并消除寄生虫引起的病理。有趣的是，雌性血吸虫只会变成 当它们与雄性蠕虫持续身体接触时，性成熟。确实，女性 在没有雄性蠕虫的情况下生长不会产生卵，不会造成严重的不良后果 在他们的主人中。尽管雄性线虫对雌性性发育的需求是 大约 100 年前就已描述过，但对于如何在 分子水平。解决这个问题的一个主要障碍是当前的文化条件不 支持血吸虫体外性发育。为了解决这个问题，我们开发了一种新颖的 支持男性诱导女性性发育和长期卵子的培养基配方 体外生产。利用这种媒介，我们做出了两个重要的观察。首先，我们 发现雌性线虫与雄性线虫配对后立即发生的基因表达变化并不 发生在生殖器官中，而是发生在寄生虫的体细胞组织中，包括神经元和 肌肉细胞。其次，我们鉴定了一种在神经系统中高度表达的转录因子 与雄性蠕虫配对后对雌性性发育至关重要的肌肉细胞。基于 根据这些数据，我们假设雌性线虫中的体细胞非生殖细胞类型是 负责感知雄性蠕虫的存在，进而调节雄性蠕虫的发育 生殖器官。定义直接负责感知存在的细胞类型 雄性线虫可以提供有关控制雄性来源信号性质的重要线索 女性性发育。因此，我们将在两个具体目标上检验我们的中心假设。在 具体目标 1 我们将描述生殖和体细胞的细胞和分子反应 使用基本发育生物学将雌性蠕虫的组织与雄性蠕虫配对 方法和单细胞RNA测序。具体目标 2 将利用 RNA 干扰和单 细胞 RNA 测序发现控制雌性所必需的基因和体细胞类型 成熟并确定这些基因如何协同作用以协调女性对 与雄性配对。我们期望这些研究能够定义刺激女性的信号事件 成熟并希望他们能提出针对血吸虫的新治疗靶点。