Plasmodium signaling of innate immunity in Anopheles

描述（由申请人提供）：斯氏按蚊一氧化氮合酶（AsNOS）介导的防御是第一次从媒介蚊子中描述的，其既由寄生虫发育天然诱导又抑制寄生虫发育。这种防御是蚊子和疟原虫的人类宿主共享的。在初步实验中，AsNOS在永生化A. stephensi细胞由来自恶性疟原虫的纯化的信号传导因子诱导。我们之前的研究表明，这种寄生虫因子足以诱导哺乳动物细胞合成炎性细胞因子和NO。通过与哺乳动物细胞的工作延伸，我们建议确定这种寄生虫因子是否是必要的和足够的模拟寄生虫激活AsNOS，并确定是否参与寄生虫信号转导AsNOS诱导的途径是保守的，与那些参与寄生虫信号转导iNOS诱导在哺乳动物细胞。最终，信号通路，中继寄生虫感染的特定信息可以直接有针对性地修改表达的AsNOS或用作工具，以确定新的下游抗寄生虫效应，可以针对疟原虫抗性按蚊的发展。

DESCRIPTION (provided by the applicant): The Anopheles stephensi nitric oxide synthase (AsNOS)-mediated defense was the first described from a vector mosquito that is both naturally induced by and inhibitory to parasite development. This defense is shared by mosquito and human hosts of Plasmodium. In preliminary experiments, AsNOS expression in immortalized A. stephensi cells was induced by a purified signaling factor from Plasmodium falciparum. Studies previous to ours demonstrated that this parasite factor is sufficient to induce the synthesis of inflammatory cytokines and NO by mammalian cells. By extension from work with mammalian cells, we propose to determine whether this parasite factor is necessary and sufficient to mimic parasite activation of AsNOS and to determine whether pathways involved in parasite signaling of AsNOS induction are conserved with those involved in parasite signaling of iNOS induction in mammalian cells. Ultimately, signaling pathways that relay specific information of parasite infection could be targeted directly to modify expression of AsNOS or used as tools to identify novel downstream anti-parasite effectors that could be targeted for the development of Plasmodium-resistant Anopheles.