ENU mutagenesis and the quest for a malaria host-directed therapy

Malaria is a disease of global concern, which causes over 800,000 deaths every year. Due to the rapid emergence of parasite drug resistance, ongoing control of malaria requires the urgent development of new anti-malarials that will have a prolonged life span. Genetic polymorphisms that provide natural resistance to malaria have existed in human populations for thousands of years without losing their efficacy. This suggests a possible new treatment strategy; drugs can be used to mimic the protective effects of such polymorphisms, in what is known as host-directed therapy (HDT). It is hoped that HDT will be able to effectively treat malaria without driving drug resistance. An ENU mutagenesis screen was established in mice to identify novel genes mediating host resistance to malaria, and to thereby uncover potential drug targets for an anti-malarial HDT. Two mutant mouse lines were investigated: MR149372, in which an over-activation of the enzyme AMPD3 causes striking resemblance to P. Chabaudi parasitaemia through high RBC turnover; and RBC10, in which an over-activation of the transporter KCC1 causes resistance to the development of cerebral malaria and modulation of the inflammatory response during P. berghei infection. Through the work in this thesis, novel insight has been gained into the role of AMPD3 in determining red blood cell half-­‐life, the effect of altered purine balance on intra-­erythrocytic parasite growth, and the host factors affecting the immune response to malaria infection. Moreover, potential novel drug targets have been identified both for lengthening the life span of blood stored for transfusion, and for treating cerebral malaria.