Pathogenesis of severe childhood malaria
This proposal aims to compare global transcriptomes from parasites isolated from a Ghanaian cohort of paediatric malaria patients with accurately defined phenotypes of the different severe malaria syndromes (n=714) with asymptomatic controls (n=250).
Malaria due to Plasmodium falciparum remains one of the major global health problems and a leading cause of death worldwide, particularly among children under the age of five. Severe childhood malaria is associated with three main overlapping syndromes: cerebral malaria, hyperlactataemia/acidosis and severe anaemia. The central feature of severe malaria, driven by host and parasite factors, is the sequestration of parasitized red blood cells in vascular beds, leading to impaired tissue perfusion and lactic acidosis. The causing agent, the parasite ligand PfEMP1, is expressed on the surface of infected red blood cells, where it binds to a broad range of different endothelial receptors. Exposure to repeated episodes of malaria infection results in the gradual acquisition of an anti-disease immunity, which targets certain PfEMP1 variants. Therefore, each parasite genome is equipped with about 60 different mutually exclusively expressed var genes to escape a gradual increasing host immunity during infection by antigenic variation. To date, no effective adjunctive therapies exist for severe malaria and the role of PfEMP1 or other parasite factors during the different and complex severe malaria syndromes is poorly understood. The RNA-seq analysis pipeline has been optimized for patient isolates and measures differences in the expression of core parasite genes as well as of the polymorphic PfEMP1-encoding var genes to provide an unprecedented in-depth analysis of clinical infections. In conclusion, the data generated in this proposal will significantly advance the scarce understanding of the complex pathology of severe malaria and will be instrumental for further studies towards identifying the molecular basis of parasite virulence.