Using magnetic resonance imaging to elucidate the mechanism of experimental cerebral malaria rescue by 6-diazo-5-oxo-norleucine

Abstract

Abstract We have previously demonstrated the efficacy of 6-diazo-5-oxo-L-norleucine (DON), a glutamine analog, as a possible adjunctive therapy to mitigate the clinical severity of human cerebral malaria (HCM) (Gordon et al. PNAS 2016). The pathology of HCM is heterogeneous, but generally includes the accumulation of infected red blood cells in the brain vascular endothelium, cerebral microhemorrhages, compromised blood-brain barrier and brain swelling. These changes manifest in severe neurologic symptoms including headache, fever, ataxia, seizures, retinopathy, and coma. The mouse model of CM, experimental cerebral malaria (ECM), approximates the main characteristics of HCM when susceptible C57BL/6 mice are infected with Plasmodium berghei ANKA (PbA) parasites. Studies in these mice found that treatment with DON, even in late stage ECM, rescued animals and increased survival while mitigating and reversing blood-brain barrier dysfunction and brain swelling. Recently, Seydel et al. (NEJM 2015) used magnetic resonance imaging (MRI) to characterize HCM pathology and correlate it to disease severity in children in Malawi. They observed increased brain volume in children that died from HCM that was uncommon in children that survived HCM. Herein, we perform MRI studies in the mouse model to determine if the disease course effectively recapitulates that of HCM, based on morphological changes in MRI. These studies may help elucidate the mechanisms underlying CM pathology, aiding the development of effective treatments. Furthermore, we utilize MRI to probe the mechanisms of action of recovery with DON treatment in order to evaluate the drug for possible clinical trials in HCM.