Cerebral Malaria and Neuronal Implications of Plasmodium Falciparum Infection: From Mechanisms to Advanced Models

Abstract

Reorganization of host red blood cells by the malaria parasite Plasmodium falciparum enables their sequestration via attachment to the microvasculature. This artificially increases the dwelling time of the infected red blood cells within inner organs such as the brain, which can lead to cerebral malaria. Cerebral malaria is the deadliest complication patients infected with P. falciparum can experience and still remains a major public health concern despite effective antimalarial therapies. Here, the current understanding of the effect of P. falciparum cytoadherence and their secreted proteins on structural features of the human blood-brain barrier and their involvement in the pathogenesis of cerebral malaria are highlighted. Advanced 2D and 3D in vitro models are further assessed to study this devastating interaction between parasite and host. A better understanding of the molecular mechanisms leading to neuronal and cognitive deficits in cerebral malaria will be pivotal in devising new strategies to treat and prevent blood-brain barrier dysfunction and subsequent neurological damage in patients with cerebral malaria. MalariaMalaria is an ancient mosquito-borne disease caused by protozoan parasites of the genus Plasmodium. According to the latest World Malaria Report published by the World Health

Clinical characteristics of platelet-mediated killing circulating parasite of major human malaria

“…Therapies with high doses of artemisinin derivatives somehow does not reduce deaths or neurological disability in the majority of cerebral malaria cases [ 30 ]. Given the parasite resistance, quinoline derivatives are even less efficient at treating severe malaria than artesunate and artemisinin derivatives [ 31 ].…”

“…Given the parasite resistance, quinoline derivatives are even less efficient at treating severe malaria than artesunate and artemisinin derivatives [ 31 ]. However, quinoline derivatives are common rapidly schizonticidal substances, which are able to reduce the mortality and mortality and alleviate the neurological cognitive deficits in cerebral malaria patients [ 30 ]. As a result, the World Health Organization has recommended combining quinoline derivatives with artemisinin-based combination therapies (ACTs).…”

“…Platelet-mediated parasite killing is one of the approaches to protect against malaria; however, the underlying mechanism involving immunity to malaria is incompletely understood. The pathogenic mechanisms of malaria, involving endothelial dysfunction [ 30 ], cell-to-cell adhesions mediated by cell-adhesion molecules and aquaporins [ 30 , 37 , 38 ], inflammatory stimuli released by activated immune cells, and sequestration of iRBC, are complex ( Figure S1 ). Traditional investigations on the pathogenic mechanism of cerebral malaria, such as brain microvascular endothelial cells culture models, membrane permeability assays, transwell systems and animal models, are poorly understood due to restrictions on replicating complicated cell-to-cell signalling, absence of unique brain microvascular features, or interspecies differences [ 30 ].…”

“…The pathogenic mechanisms of malaria, involving endothelial dysfunction [ 30 ], cell-to-cell adhesions mediated by cell-adhesion molecules and aquaporins [ 30 , 37 , 38 ], inflammatory stimuli released by activated immune cells, and sequestration of iRBC, are complex ( Figure S1 ). Traditional investigations on the pathogenic mechanism of cerebral malaria, such as brain microvascular endothelial cells culture models, membrane permeability assays, transwell systems and animal models, are poorly understood due to restrictions on replicating complicated cell-to-cell signalling, absence of unique brain microvascular features, or interspecies differences [ 30 ]. 3D bioprinting approaches remain some challenges, while this technological application will be the in vitro studies of cerebral malaria in the future.…”

Mechanism of Immune Evasion in Mosquito-Borne Diseases

“…Neurological disorder : P. falciparum -mediated malaria is known to cause cerebral malaria, a severe disease that can result in neurological complications such as seizures, loss of consciousness, and coma [ 132 ]. The pathogenesis of cerebral malaria involves the sequestration of infected erythrocytes in the brain microvasculature and the resulting immune response, leading to endothelial damage, vascular leakage, and hypoxia.…”