Evidence from a natural experiment that malaria parasitemia is pathogenic in retinopathy-negative cerebral malaria

Abstract

Cerebral malaria (CM) can be classified as retinopathy-positive or retinopathy-negative, based on the presence or absence of characteristic retinal features. While malaria parasites are considered central to the pathogenesis of retinopathy-positive CM, their contribution to retinopathy-negative CM is largely unknown. One theory is that malaria parasites are innocent bystanders in retinopathy-negative CM and the etiology of the coma is entirely non-malarial. Because hospitals in malaria-endemic areas often lack diagnostic facilities to identify non-malarial causes of coma, it has not been possible to evaluate the contribution of malaria infection to retinopathy-negative CM. To overcome this barrier, we studied a natural experiment involving genetically inherited traits, and find evidence that malaria parasitemia does contribute to the pathogenesis of retinopathy-negative CM. A lower bound for the fraction of retinopathy-negative CM that would be prevented if malaria parasitemia were to be eliminated is estimated to be 0.93 (95% confidence interval: 0.68, 1).DOI: http://dx.doi.org/10.7554/eLife.23699.001

MRI demonstrates glutamine antagonist-mediated reversal of cerebral malaria pathology in mice

“…Previously, it was widely believed that venous occlusion caused by sequestered infected RBCs (iRBCs) was solely responsible for generating pathology, but mortality remains high even with the implementation of fastacting antimalarials like artemisinin combination therapies (51)(52)(53). There is increasing evidence that both the cerebral vascular sequestration and host immune response contribute to neuropathology (54)(55)(56). Ultimately, downward herniation of the brainstem as a result of increased intracranial pressure leads to rapid death in these patients, and the expeditious reversal of this edema may dramatically reduce mortality.…”

Parasite histones mediate leak and coagulopathy in cerebral malaria

“…Inclusion criteria are described previously (8). Children who met WHO criteria for CM underwent funduscopic examination by an ophthalmologist: characteristic retinal changes indicate sequestration of IE in the brain(37) and distinguish retinopathy-positive CM with stringently defined CM (CM-pos) from cases with retinopathy negative CM (CM-neg), who are more likely to have an alternative diagnosis (1), to which malaria makes a variable contribution (38) and thus may have a different coma aetiology. Venous blood was collected at admission into plain or sodium citrate tubes and serum and plasma prepared as previously described(39), stored at −80°C until assays were performed.…”

Transcriptomic Studies of Malaria: a Paradigm for Investigation of Systemic Host-Pathogen Interactions

“…The pathogenesis of human cerebral malaria (CM) has been extensively debated because it is currently impossible to prove the dependency of the syndrome on any specific pathogenic mechanism. In contrast to the widely used P. berghei ANKA C57BL/6 ECM model, human CM may not even be a single entity but may have several pathological subtypes ( 181 – 184 ). The first of these subtypes is not CM at all but “false CM,” with coma being due to another cause (infectious or noninfectious) in the presence of incidental parasitemia ( 181 ).…”

“…A relatively common and specific feature of CM that is not present in false CM is malarial retinopathy, which colocalizes with the sequestration of parasites in the retinal blood vessels ( 181 , 185 ). This has been used to define children with true CM, but it has become apparent that coma in some children without retinopathy is also at least partly caused by malaria ( 182 , 183 , 186 ).…”