Snail-Related Studies of Transmission and Control of Schistosomiasis in Kenya

描述(申请人提供)：由于血吸虫病的地方性和慢性性质，相对于其他更明显和更广为人知的传染病，很容易被忽视。它是一种真正被忽视和无法征服的热带疾病，我们一直低估了它对健康的影响。我们控制它的手段几乎是不够的，我们处理它的专业知识有限，而且正在萎缩。血吸虫在蜗牛体内经历了强制性的幼虫发育，在这些幼虫中，它们产生了数量惊人的人类感染的尾蚴。控制项目几乎只专注于用一种广泛获得的药物吡喹酮来治疗患者，但基于药物的控制一直未能阻断传播，因为它忽视了蜗牛在支持血吸虫生命周期中的核心作用。世界上90%以上的血吸虫病患者生活在撒哈拉以南非洲，其中最主要的致病物种之一是曼氏血吸虫。这项提案侧重于曼氏血吸虫与其最常见的非洲钉螺宿主--Pfeifferi之间的相互作用，因为它们共同出现在肯尼亚。我们将提供有关钉螺在传播中的作用以及如何开发新的控制方法来补充现有的以药物为中心的单一计划的新信息。在整个项目中，重点将是直接从活跃的传播点采集的pfeifferi钉螺，以及它们与直接来自附近受感染儿童的曼氏毛滴虫的相互作用。我们的四个目标是一致的，因为需要定义野生蜗牛和血吸虫种群之间存在的相容程度，以及控制这种相容程度的因素。在我们已经进行的工作的基础上，我们已经确定了蜗牛基因在控制兼容性方面的重要作用，我们将在实验室尝试改变这些基因在田间蜗牛中的表达，以了解我们是否可以降低兼容性。这将为进一步的研究开辟道路，在这些研究中，可以操纵蜗牛的兼容性来帮助控制努力。此外，认识到人类传染病的影响可以通过生态制衡来减少，我们还将探索天敌，包括竞争物种的双基因吸虫，在限制曼氏葡萄球菌与pfeifferi的兼容性和流行率方面所发挥的被低估的作用。最后，通过应用现代技术，如微阵列分析和深度测序，我们试图定义蜗牛对感染的反应，并突出受感染蜗牛的生理脆弱性，使我们能够更好地利用这些弱点，在控制努力中选择性地消除它们。这项研究是新颖的，因为它强调将现代分子方法应用于非洲背景下的野生蜗牛和血吸虫，而不是停留在实验室模型上。此外，该项目旨在为BOT肯尼亚和美国博士生提供培训，以保持我们在一个调查人员数量急剧减少的领域的专业知识。我们的工作最终将有利于在世界上最迫切需要血吸虫病控制的热带非洲地区发展更可持续和更成功的血吸虫病控制手段。

DESCRIPTION (provided by applicant): Because of its endemic and chronic nature, schistosomiasis is easy to overlook relative to other more visible and publicized infectious diseases. It is a truly neglected and unconquered tropical disease, one for which we have consistently underestimated its health impact. Our means to control it are barely adequate and our expertise for dealing with it is limited and shrinking. Schistosomes undergo obligatory larval development in snails in which they produce human- infective cercariae in prodigious numbers. Control programs focus almost exclusively on treating people with the one widely available drug, praziquantel, yet drug-based control consistently fails to interrupt transmission because it ignores the central role of snails in supporting the schistosome life cycle. Over 90% of the world's victims of schistosomiasis live in sub-Saharan Africa, with one of the most prominent causal species being Schistosoma mansoni. This proposal focuses on the interactions between S. mansoni and its most common African snail host, Biomphalaria pfeifferi, as they co-occur in Kenya. We will provide new information regarding the role of snails in transmission, and how new methods of control could be developed to complement the existing uni-dimensional drug-centered programs. Throughout this project, the emphasis will be on B. pfeifferi snails taken straight from an active transmission site, and their interactions with S. mansoni miracidia derived directly from nearby infected children. Our four aims are united by the need to define the degree of compatibility that exists between wild snail and schistosome populations, and the factors that govern that level of compatibility. Building on work we have undertaken that has identified snail genes important in governing compatibility, we will attempt in the lab to alter expression of these genes in field- derived snails to learn if we can diminish compatibility. This would open the way for further studies in which snail compatibility might be manipulated to assist control efforts. Also, acknowledging that the impact of human infectious diseases can be reduced by ecological checks and balances, we will also explore the underappreciated role of natural enemies, including competing species of digenetic trematodes, in limiting S. mansoni's compatibility with, and prevalence in, B. pfeifferi. Finally, by applying modern techniques like microarray analysis and deep sequencing, we seek to define how snails respond to infection and to highlight physiological vulnerabilities of infected snails to enable us to better exploit thse weaknesses to selectively eliminate them in control efforts. This study is novel for its emphasis on applying modern molecular methods to wild snails and schistosomes in the African context, instead of dwelling on lab models. Also, this project is oriented around providing training for bot Kenyan and U.S. PhD students to maintain our expertise in an area that is suffering from a sharply dwindling number of investigators. Our work will ultimately favor development of more sustainable and successful means of schistosomiasis control in the part of the world where it is most urgently needed, tropical Africa.