Freitas Tori C, Jung Euihye, Pearce Edward J
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
PLoS Pathog. 2007 Apr;3(4):e52. doi: 10.1371/journal.ppat.0030052.
Over 200 million people have, and another 600 million are at risk of contracting, schistosomiasis, one of the major neglected tropical diseases. Transmission of this infection, which is caused by helminth parasites of the genus Schistosoma, depends upon the release of parasite eggs from the human host. However, approximately 50% of eggs produced by schistosomes fail to reach the external environment, but instead become trapped in host tissues where pathological changes caused by the immune responses to secreted egg antigens precipitate disease. Despite the central importance of egg production in transmission and disease, relatively little is understood of the molecular processes underlying the development of this key life stage in schistosomes. Here, we describe a novel parasite-encoded TGF-beta superfamily member, Schistosoma mansoni Inhibin/Activin (SmInAct), which is key to this process. In situ hybridization localizes SmInAct expression to the reproductive tissues of the adult female, and real-time RT-PCR analyses indicate that SmInAct is abundantly expressed in ovipositing females and the eggs they produce. Based on real-time RT-PCR analyses, SmInAct transcription continues, albeit at a reduced level, both in adult worms isolated from single-sex infections, where reproduction is absent, and in parasites from IL-7R(-/-) mice, in which viable egg production is severely compromised. Nevertheless, Western analyses demonstrate that SmInAct protein is undetectable in parasites from single-sex infections and from infections of IL-7R(-/-) mice, suggesting that SmInAct expression is tightly linked to the reproductive potential of the worms. A crucial role for SmInAct in successful embryogenesis is indicated by the finding that RNA interference-mediated knockdown of SmInAct expression in eggs aborts their development. Our results demonstrate that TGF-beta signaling plays a major role in the embryogenesis of a metazoan parasite, and have implications for the development of new strategies for the treatment and prevention of an important and neglected human disease.
超过2亿人感染了血吸虫病，另有6亿人面临感染风险，血吸虫病是主要的被忽视热带病之一。这种由血吸虫属蠕虫寄生虫引起的感染传播，取决于寄生虫卵从人类宿主中释放。然而，血吸虫产生的虫卵约有50%未能到达外部环境，而是被困在宿主组织中，在那里，对分泌的虫卵抗原的免疫反应引起的病理变化会引发疾病。尽管产卵在传播和疾病中至关重要，但对于血吸虫这一关键生命阶段发育的分子过程，人们了解得相对较少。在此，我们描述了一种新的寄生虫编码的转化生长因子-β超家族成员，曼氏血吸虫抑制素/激活素（SmInAct），它是这一过程的关键。原位杂交将SmInAct的表达定位到成年雌性的生殖组织，实时逆转录聚合酶链反应分析表明，SmInAct在产卵雌性及其产生的虫卵中大量表达。基于实时逆转录聚合酶链反应分析，在从无生殖的单性感染中分离出的成虫以及来自IL-7R(-/-)小鼠（其产生活虫卵的能力严重受损）的寄生虫中，SmInAct转录仍会继续，尽管水平有所降低。然而，蛋白质免疫印迹分析表明，在来自单性感染和IL-7R(-/-)小鼠感染的寄生虫中检测不到SmInAct蛋白，这表明SmInAct的表达与蠕虫的生殖潜力紧密相关。发现通过RNA干扰介导的SmInAct在虫卵中的表达敲低会导致其发育中止，这表明SmInAct在成功的胚胎发生中起关键作用。我们的结果表明，转化生长因子-β信号传导在一种后生动物寄生虫的胚胎发生中起主要作用，并对开发治疗和预防一种重要且被忽视的人类疾病的新策略具有启示意义。
