Host and parasite factors associated with brain swelling in pediatric cerebral malaria

Abstract

Malaria is a mosquito-borne illness caused by Plasmodium spp . parasites. In 2013, there was an estimate of 198 million malaria cases with 584,000 deaths worldwide. In infections with P. falciparum , cerebral malaria (CM), a complication involving impaired consciousness is observed, with a mortality rate of about 19% despite the administration of treatment. The mechanism of CM is not well understood but recently, it was demonstrated that pediatric CM patients with severe brain swelling at admission were 14 times more likely to die. This makes brain swelling the strongest predictor of death in pediatric CM. Understanding host or parasite biology associated with brain swelling will inform adjuvant therapies in CM. The work in this thesis examines host plasma markers associated with CM brain swelling and characterizes a putative P. falciparum phospholipase A2 (pfPLA2), whose transcripts correlate to CM brain swelling.;We identified phospholipase A2 (PLA2) metabolites and plasma PLA2 activity to correlate with brain swelling. PLA2 enzymes are implicated in inflammation by producing arachidonic acid; a precursor of inflammatory mediators. Moreover, we identified an association between plasma pro-inflammatory cytokines and brain swelling. Additionally, transcription of pfPLA2 was associated with brain swelling. Therefore, we compare the sequence homology of pfPLA2 to other species. Furthermore, we demonstrate that pfPLA2 is expressed in all the intraerythrocytic life stages of the parasite and is localized in the cytosol and perinuclear space. Finally, we show that a PLA2 inhibitor can kill P. falciparum cultures of geographically diverse strains.;Our results suggest that an excessive inflammatory response is associated with CM brain swelling. More importantly, our data identify the PLA2 pathway to be implicated in severe brain swelling. The role of PLA2 in CM pathogenesis can now be studied to inform adjunct therapy development for CM patients with severe brain swelling. Furthermore, we identify pfPLA2 transcripts to be associated with brain swelling; and present studies of its sequence homology, cell biology and drug inhibition. The role of pfPLA2 in the development of brain swelling warrants further examination. In conclusion, this work has expanded the knowledge regarding host inflammation during CM and identified a potential novel antimalarial target.