Dissection of Anopheles Responses to Plasmodium Infected Blood

按蚊对疟原虫感染血液反应的剖析

• 批准号: 7887058
• 负责人: George Dimopoulos
• 金额: $ 41万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7887058
• 关键词: Address; Anopheles Genus; Applied Genetics; Bacteria; Biological Assay; Blood; Computer Systems Development; Culicidae; Development; Disease; Dissection; Exposure to; Genes; Genetic; Goals; Human; Immune; Immune response; Immune system; Infection; Insecta; Life Cycle Stages; Link; Malaria; Mediating; Microbe; Molecular; Mosquito Control; NF-kappa B; Natural Immunity; Nature; Nuclear Translocation; Parasites; Pathway interactions; Phenotype; Plasmodium; Plasmodium falciparum; Publishing; RNA Interference; Refractory; Regulation; Research; Research Proposals; Resistance; Resistance development; Signal Pathway; Staging; Study models; System; Time; Tissues; Transgenes; Transgenic Organisms; Virus; combinatorial; cost; fight against; fitness; functional genomics; fungus; interest; killings; microbial; pathogen; public health relevance; response; tool; trait; transcription factor

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.

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抵御疟原虫的主要防线。这些免疫反应主要受 TOLL 和 IMD 途径调节，它们分别控制 NF-κB 样转录因子 Rel1 和 Rel2 的核转位。虽然这两种途径都与抗疟原虫防御有关，但我们已经证明，IMD 途径在调节几种按蚊​​物种对多种疟原虫物种（包括人类病原体恶性疟原虫）的抵抗力方面发挥着保守的关键作用。我们已经证明，Rel2 转录因子通过多个效应器介导抗疟原虫作用，并且瞬时诱导 Rel2 激活的适应成本最小。因此，IMD 途径对于转基因抗疟原虫蚊子的开发特别有意义。该提案将侧重于更好地了解 Rel2 介导的疟原虫耐药性，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 Rel2 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来对抗包括疟原虫寄生虫在内的多种微生物病原体。我们已经证明 IMD 免疫信号通路是抗疟原虫防御的主要参与者。本研究计划旨在对冈比亚疟原虫中 IMD 途径介导的疟原虫抗性进行分子剖析。