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

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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.