Dissection of Anopheles Responses to Plasmodium Infected Blood

描述(申请人提供)：先天免疫系统是蚊子在疟疾寄生虫生命周期的多个阶段对抗疟疾寄生虫的主要防线。这些免疫反应在很大程度上受Toll和IMD途径的调控，这两条途径分别控制着核转录因子-kappaB样转录因子Rel1和Rel2的核转位。虽然这两条途径都与抗疟原虫防御有关，但我们已经证明，IMD途径是调节几种按蚊对多种疟疾寄生虫包括人类病原体恶性疟原虫的抵抗力的保守关键角色。我们已经证明了Rel2转录因子通过多个效应器介导的抗疟原虫作用，并且瞬时诱导Rel2激活的适应成本是最小的。因此，IMD途径对于转基因抗疟原虫蚊子的发展特别感兴趣。这项提案将侧重于更好地了解Rel2介导的对疟疾的抗药性，从而评估将这一系统用于制定疟疾控制战略的可行性。该项目的总体目标是开发能够在感染的适当阶段激活Rel2介导的抗疟原虫防御的转基因蚊子。这些蚊子将被用来研究这种防御系统的调节，并剖析导致疟原虫死亡的基因和机制。

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.