Dissection of Anopheles Responses to Plasmodium Infected Blood

描述（由申请人提供）：先天免疫系统是蚊子在疟原虫生命周期的多个阶段对抗疟原虫的主要防线。这些免疫应答主要由TOLL和IMD途径调节，它们分别控制NF-κ B样转录因子Rel 1和Rel 2的核转位。虽然这两种途径都涉及抗疟原虫防御，但我们已经表明IMD途径是调节几种按蚊对多种疟疾寄生虫物种（包括人类病原体恶性疟原虫）的抗性的保守关键因素。我们已经表明，Rel 2转录因子介导的抗疟原虫的行动，通过多个效应器和健身成本的短暂诱导Rel 2激活是最小的。因此，IMD途径对于遗传修饰的抗疟原虫蚊子的开发特别有趣。该提案将侧重于更好地了解Rel 2介导的疟原虫抗性，从而评估使用该系统制定疟疾控制策略的可行性。该项目的总体目标是开发能够在感染的适当阶段激活Rel 2介导的抗疟原虫防御的转基因蚊子。这些蚊子将用于研究这种防御系统的调节，并剖析负责杀死疟原虫的基因和机制。 公共卫生相关性：按蚊利用其先天免疫系统对抗包括疟原虫在内的广泛的微生物病原体。我们已经表明，IMD免疫信号通路是抗疟原虫防御的主要参与者。本研究旨在从分子水平上研究IMD途径介导的疟原虫对疟原虫的抗性。冈比亚。

DESCRIPTION (provided by applicant): The innate immune system is the mosquito's main line of defense against the malaria parasite Plasmodium at multiple stages of the parasite's life cycle. These immune responses are largely regulated by the TOLL and IMD pathways, which control the nuclear translocation of the NF-kappaB-like transcription factors, Rel1 and Rel2, respectively. While both pathways are implicated in anti-Plasmodium defense, we have shown that the IMD pathway is a conserved key player in regulating resistance of several Anopheles species to multiple malaria parasite species including the human pathogen P. falciparum. We have shown that the Rel2 transcription factor - mediate anti- Plasmodium action through multiple effectors and that the fitness cost of a transient induction of the Rel2 activation is minimal. As such, the IMD pathway is particularly interesting for the development of genetically modified Plasmodium resistant mosquitoes. This proposal will focus on a better understanding of the Rel2 mediated resistance to Plasmodium and thereby assess the feasibility to use this system for the development of malaria control strategies. The overall aim of this project is to develop transgenic mosquitoes that can activate Rel2 mediated anti-Plasmodium defense at an appropriate stage of infection. These mosquitoes will be used to study the regulation of this defense system and dissect the genes and mechanisms that is responsible for Plasmodium killing. PUBLIC HEALTH RELEVANCE: The Anopheles mosquito uses its innate immune system to fight against a broad spectrum of microbial pathogens including the Plasmodium parasite. We have shown that the IMD immune signaling pathway is a major player in anti-Plasmodium defense. This research proposal aims at the molecular dissection of IMD pathway mediated Plasmodium resistance in A. gambiae.