Molecular Aspects of Tsetse and Trypanosome Transmission

描述（由申请方提供）：非洲锥虫再次成为非洲大部分地区的主要公共卫生问题。由于缺乏哺乳动物疫苗和有效且负担得起的药物，控制策略受到限制。重组DNA技术的最新发展有助于改善现有的病媒控制措施，但由于缺乏关于采采蝇分子方面及其与锥虫相互作用的信息，这方面的进展受到阻碍。采采蝇一般对非洲锥虫的传播不敏感，尽管不敏感的分子基础尚不清楚。预先诱导采采蝇免疫系统可以减少寄生虫的传播，表明采采蝇的先天防御监视系统能够终止锥虫的发育。在这里提出的工作中，将使用几种不同的分子策略鉴定一组全面的免疫应答基因，并分析它们在不同免疫挑战中的表达谱。分别由脂肪体和腺胃组织介导的全身和局部反应将在分子水平上进行研究。提出了几个关键的抗菌基因产物的功能研究，以了解它们在寄生虫传播中的作用。这项研究将使我们开始了解采采蝇免疫系统的组成部分，以及它们在寄生虫建立和传播过程中与锥虫的相互作用。虽然生殖系转化方法是困难的，因为它不寻常的繁殖生物学，在采采蝇，特别是Sodalis glossinidius的肠道共生体中的转基因表达，可能被证明是一个有价值的策略，以控制疾病的传播。这种策略的核心将是鉴定用作转基因的合适基因。免疫基因是强有力的候选者，这项研究可能有助于识别。这些基因也可能在锥虫的分化中发挥作用，该项目将再次确定潜在的候选者。

DESCRIPTION (provided by the applicant): African trypanosomiasis is once again a major public health problem throughout much of Africa. Control strategies are limited due to the lack of mammalian vaccines and efficacious and affordable drugs. The recent developments in recombinant DNA technologies stand to improve existing vector control measures, but progress in this are has been hampered by the lack of information on the molecular aspects of tsetse and its interactions with trypanosomes. Tsetse flies are in general refractory to the transmission of African trypanosomes although the molecular basis for refractoriness is unknown. Prior induction of the tsetse immune system can reduce parasite transmission indicating that tsetse's innate defense surveillance system is capable of terminating the development of trypanosomes. In the work proposed here, a comprehensive panel of immune-responsive genes will be identified using several different molecular strategies and their expression profiles in response to different immune challenges will be analyzed. Both systemic and local responses, respectively mediated by fat body and proventriculus tissue, will be investigated at the molecular level. Functional studies are proposed with several key antimicrobial gene products to understand their role in parasite transmission. This study will allow us to begin to understand the components of the tsetse immune system and the interactions they exhibit with trypanosomes during the parasite establishment and transmission in the fly. Although germ line transformation approach is difficult in tsetse because of its unusual reproductive biology, expression of transgenes in the gut symbionts of tsetse, particularly Sodalis glossinidius, may prove a valuable strategy to control disease transmission. Central to such a strategy will be identification of suitable genes for use as transgenes. Immunity genes are strong candidates, which this study may help to identify. These genes may also play a role in differentiation of trypanosomes and again, this project will identify potential candidates.