Underlying mechanisms of schistosome/snail compatibility

描述（由申请人提供）：本修订提案旨在支持一项由免疫学家发起的研究项目，该项目旨在研究人类寄生虫中间宿主用于免疫攻击和杀死这些寄生虫的细胞和分子手段。广泛的长期目标是打破寄生虫向高危人群传播的循环。该研究建立在申请人实验室和其他实验室的最新进展的基础上，并利用了比较功能基因组学的原理和宿主蜗牛基因组的新兴数据库。特别是，研究涉及细胞呼吸爆发的基因，信使RNA和蛋白质-一个复杂的途径，其中有害的活性氧和氮物质由宿主的防御细胞产生，并且至少部分负责个体蜗牛抵抗感染的能力。这些目标解决了以下可能的假设：（i）基因：基因结构，转录和转录后编辑的细节，（ii）蛋白质（包括酶活性），（iii）细胞反应的激活途径，以及（iv）孢子囊死亡的最终原因。这些假说既易于处理，又合理地扎根于已经证明的现象中。实验材料包括已知对曼氏血吸虫标准株（俄勒冈州PR 1）敏感或耐药的个体光滑双脐螺（Biomphalaria glabrata），曼氏血吸虫是人类肠道血吸虫病的病原体。资金将使一个研究小组能够在5年内集中精力研究这些问题。从这些研究中获得的知识有望提高实现该机构使命的可能性--预防寄生虫的未来传播（S。mansoni）传播给人类-通过中断寄生虫在其中间宿主B中的生命周期来实现。光滑的这些目标将使用中间宿主蜗牛物种的近交系来解决，我们有必要的遗传信息（核酸序列数据），并且现在可以使用敏感的报告和各种细胞功能的有效抑制剂。 公共卫生相关性：这种（人血吸虫）寄生虫的负担在流行地区的人群中相当大（超过70个国家，其中约有2亿人感染）。感染者的认知水平较低（学习更困难），体力劳动的能量也较低。因此，这项工作的最终目标是打破恶性传播的循环，通过提高健康和生活质量（提高学习和从事体力劳动的能力），可能有助于公共福利。

DESCRIPTION (provided by applicant): This revised proposal seeks support for an investigator-initiated research project into the cellular and molecular means used by intermediate hosts of a human parasite to immunologically attack and kill these parasites. The broad, long-term objective is to break the cycle of parasite transmission to at-risk human populations. The research builds on recent progress in the applicant's laboratory and other laboratories, and exploits the principles of comparative functional genomics and an emerging database for the host snail's genome. In particular, the research deals with genes, messenger RNAs and proteins involved in the cellular respiratory burst - a complex pathway in which damaging reactive oxygen and nitrogen species are produced by the defense cells of the host and which are at least partialy responsible for the capacity of individual snails to resist infection. The aims address plausible hypotheses dealing with (i) genes: details of gene structure, transcription and post-transcriptional editing, (ii) proteins (including enzyme activities), (iii) activation pathways for cell responses, and (iv) ultimate causes of death of sporocysts. The hypotheses are both tractable and reasonably anchored in already demonstrated phenomena. Experimental materials include individual Biomphalaria glabrata snails with known susceptible or resistant phenotypes to a standard strain (Oregon PR1) of Schistosoma mansoni, a causative agent of human intestinal schistosomiasis. Funds will enable a team of researchers to focus their efforts on these issues over 5 years. Knowledge resulting from the studies is expected to enhance the likelihood of achieving a mission of this agency - prevention of future transmission of schistosome parasites (S. mansoni) to humans - accomplished by interruption of the parasite's life cycle in its intermediate host, B. glabrata. These goals will be addressed using inbred strains of the intermediate host snail species for which we have the necessary genetic information (nucleic acid sequence data) and in which it is now feasible to use sensitive reporters for and efficient inhibitors of a variety of cell functions. PUBLIC HEALTH RELEVANCE: The burden of this (human blood-fluke) parasite is considerable among human populations in endemic regions (>70 countries in which ~200,000,000 people are infected). Infected individuals experience lower levels of cognition (it is harder to learn), and of energy to do physical work. Hence this work, in which the ultimate aim is to break the cycle of schistosome transmission, may contribute to public welfare through enhancement of health and of the quality of life (improved capacities to learn and to do physical work).