Identifying new insecticidal targets against Plasmodium falciparum infected Anopheles gambiae to fight malaria employing systems biology approaches

采用系统生物学方法，针对感染恶性疟原虫的冈比亚按蚊确定新的杀虫靶标，以对抗疟疾

• 批准号: 347509908
• 负责人: Professor Dr. Rainer König
• 金额: --
• 依托单位: International Centers of Excellence in Research (ICER)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/347509908?language=en
• 关键词: Identifying; new; insecticidal; targets; against

Malaria is a major public health problem associated with high mortality, morbidity rates and undue economic burden in sub-Saharan countries. The most fatal and prevalent form of malaria is caused by the blood-borne pathogen Plasmodium falciparum, whose transmitting vector is Anopheles gambiae. Most approaches follow the obvious strategy to fight malaria by harming the parasite directly. However, this comes along with severe resistance problems and there is the urgent need for new methods to control malaria. We will follow a rather neglected course. We will tackle malaria spread by targeting the vector (An. gambiae), and more specifically, the infected form of the vector. Strikingly, regarding microbial - host interactions in human and animal models, pathogens and the host often mutually develop tolerance strategies which can be beneficial for the pathogen and the host. Instead of a clearance of the pathogen by host immune cells, the pathogen penetrates host cells like osteoblasts, the lung or the liver and induces tolerance mechanisms that allow the host cell and the microorganism to survive. We want to rather interfere such tolerance mechanisms in the vector to induce or revoke resistance mechanisms. The aim of the project is to - develop and investigate gene regulatory networks for signaling and metabolism to identify genes being central for the induction of the immune response in the midgut of P. falciparum infected An. gambiae, - find targets which, when targeted, will reprogram regulation of metabolism and signaling of the vectors midgut cells to enhance the recognition of the pathogen and hence induction of the immune response of the vector, and- to experimentally validate these predictions.We aim to find drug targets in the vector which, when targeted, will induce an inflammatory shock. This increases the risk of death of the whole organism or leads to parasitic clearance. Both of which is beneficial for reducing the spread of malaria. For this, we need an in-depth understanding of the regulation of the immune response of the mosquitoes, and in particular how the cells organize their proteins into pathways of interacting signal transduction, regulation and metabolism. Using pathway information from reported reconstructions, own developments, and databases, we will investigate construct signaling, regulation and metabolic models, and apply well established computational models. We will integrate experimental gene expression data into these models and simulate loss of function of signaling molecules and enzymes coming up with potential drug targets reprogramming the joint system when targeted. These targets will be experimentally validated by functional perturbation assays. Until now, nobody has investigated the interplay between An. gambiaes immune response and the parasite on a systems view, which will be approached by this project leading to new targets for specific insecticidal development.

疟疾是撒哈拉以南非洲国家的一个主要公共卫生问题，与高死亡率、高发病率和过度的经济负担有关。最致命和最普遍的疟疾形式是由血液传播病原体恶性疟原虫引起的，其传播媒介是冈比亚按蚊。大多数方法都遵循通过直接伤害寄生虫来对抗疟疾的明显策略。然而，这沿着而来的是严重的耐药性问题，迫切需要新的方法来控制疟疾。我们将遵循一条相当被忽视的道路。我们将通过针对病媒来解决疟疾传播问题。冈比亚），更具体地，是载体的感染形式。引人注目的是，关于人类和动物模型中的微生物-宿主相互作用，病原体和宿主通常相互发展耐受性策略，这可能对病原体和宿主有益。病原体不是通过宿主免疫细胞清除病原体，而是穿透宿主细胞如成骨细胞、肺或肝，并诱导耐受机制，使宿主细胞和微生物存活。我们希望在载体中干扰这种耐受机制，以诱导或撤销抗性机制。该项目的目的是开发和研究信号和代谢的基因调控网络，以确定在恶性疟原虫感染的中肠中诱导免疫反应的基因。冈比亚，-找到靶点，当被靶向时，将重新编程载体中肠细胞的代谢和信号传导的调节，以增强对病原体的识别，从而诱导载体的免疫应答，并且-实验验证这些预测。这增加了整个生物体死亡的风险或导致寄生虫清除。这两者都有利于减少疟疾的传播。为此，我们需要深入了解蚊子免疫反应的调节，特别是细胞如何将其蛋白质组织成相互作用的信号转导，调节和代谢途径。使用来自报告的重建，自己的发展和数据库的途径信息，我们将研究构建信号，调节和代谢模型，并应用完善的计算模型。我们将把实验基因表达数据整合到这些模型中，并模拟信号分子和酶的功能丧失，从而提出潜在的药物靶点，在靶向时重新编程关节系统。这些目标将通过功能扰动测定进行实验验证。到目前为止，还没有人调查过安之间的相互作用。冈比亚的免疫反应和寄生虫的系统观点，该项目将探讨这一点，从而为具体的杀虫剂开发找到新的目标。