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

Treatments for malaria rapidly lose effectiveness due to parasite adaption. Using naturally occurring resistance to malaria as an example, it may be possible to circumvent this adaption by developing antimalarial therapies which render the host impervious to infection, rather than directly disabling the parasite. Known as host directed therapy, the success of this strategy depends on a detailed understanding of host factors which are critical to parasite survival. An N-ethyl-N-nitrosourea (ENU) mutagenesis screen facilitated identification of two novel genes which influence malaria susceptibility in mice, Tfrc and Sptb. Mutations in these genes increased and decreased susceptibility to Plasmodium chabaudi infection respectively. In order to determine the mechanisms underpinning this susceptibility, a novel assay was developed based on flow cytometry of fluorescently labelled erythrocytes, and a dual staining approach towards the identification of parasitized erythrocytes. Using this assay it was determined that for Tfrc, which encodes the iron transport protein transferrin receptor 1, intraerythrocytic parasite survival was enhanced. For Sptb, which encodes erythrocytic beta spectrin, parasitized erythrocytes were found to be more susceptible to phagocytosis. Overall, the study of these mutations and the mechanisms by which they influence malaria susceptibility has resulted in an increased understanding of host factors involved in this deadly disease. In future, it may be possible to manipulate these mechanisms to develop a host directed therapy, which would be less prone to parasite drug resistance.