Investigation of a novel host-directed therapy for malaria through ENU mutagenesis

Malaria, caused by the Plasmodium parasite, remains one of the top deadly infectious diseases worldwide. Currently the only way to treat malaria is with drugs that are directed against the parasite. However, the development of resistant parasites to all these antimalarials is a growing concern. Therefore, new strategies are needed for drugs that are not affected by resistant parasites. A clue has been provided by so called “natural genetic antimalarials”. Over millennia, exposure to the parasite has led to the evolution of several genetic mutations in the human genome that offer stable protection against infection. Unfortunately many of these gene polymorphisms have been associated with other, often lethal, side-effects. Therefore, the aim of this thesis was to identify novel protective genes and biochemical pathways that may be targeted to provide a novel and more lasting host-directed therapy (HDT) for malaria. We employed a large scale ENU (N-Ethyl-N-Nitrosourea) based gene-driven mutagenesis screen in a mouse model to assist in the discovery of potential new drug targets for an HDT. Several novel single point mutations in a number of gene candidates were identified and experiments conducted to reveal the associated phenotype highlighting the biological function behind the affected gene. Further, the mode of action of the acquired resistance was examined and demonstrated. Overall, the work presented here contributes to a better understanding of host-parasite interactions in malaria. Further, this thesis offers proof of the principle that targeting the host is an effective strategy in the discovery of a new generation of antimalarials that may not be limited by drug resistant parasites.