Review
doi: 10.3389/fcimb.2022.939532.
eCollection 2022.
Cerebral malaria induced by plasmodium falciparum: clinical features, pathogenesis, diagnosis, and treatment
Xiaonan Song
1
, Wei Wei
2
, Weijia Cheng
1
, Huiyin Zhu
1
, Wei Wang
3
, Haifeng Dong
4
, Jian Li
1
Affiliations
- PMID: 35959375
- PMCID: PMC9359465
- DOI: 10.3389/fcimb.2022.939532
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Review
Cerebral malaria induced by plasmodium falciparum: clinical features, pathogenesis, diagnosis, and treatment
Xiaonan Song et al.
Front Cell Infect Microbiol.
.
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Abstract
Cerebral malaria (CM) caused by Plasmodium falciparum is a fatal neurological complication of malaria, resulting in coma and death, and even survivors may suffer long-term neurological sequelae. In sub-Saharan Africa, CM occurs mainly in children under five years of age. Although intravenous artesunate is considered the preferred treatment for CM, the clinical efficacy is still far from satisfactory. The neurological damage induced by CM is irreversible and lethal, and it is therefore of great significance to unravel the exact etiology of CM, which may be beneficial for the effective management of this severe disease. Here, we review the clinical characteristics, pathogenesis, diagnosis, and clinical therapy of CM, with the aim of providing insights into the development of novel tools for improved CM treatments.
Keywords: Plasmodium falciparum; blood–brain barrier; cerebral malaria; clinical manifestation; clinical treatment; neurological damage.
Copyright © 2022 Song, Wei, Cheng, Zhu, Wang, Dong and Li.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Figures
Schematic of experimental cerebral malaria (ECM) pathogenesis. The ECM is initiated by dendritic cells (DCs) processing and presenting infected red blood cell (iRBC) antigens to CD4+ and CD8+ T cells in the spleen (1). NK cells and macrophages are activated by iRBCs to secrete inflammatory cytokines (2). The iRBCs adhere to endothelial cells (ECs) of the brain microvasculature through the interaction between P. falciparum erythrocyte membrane protein-1 (PfEMP-1) of iRBCs and cell adhesion molecules of ECs (3). The adhesion of iRBCs to the cerebral microvascular endothelium is also further accompanied by agglutination to other iRBCs, platelets, white blood cells (WBCs), and the rosetting effect formed by the adhesion of iRBCs and RBCs. ECs are activated by interactions with iRBCs and responses to inflammatory cytokines. Activated ECs promote the upregulation of cell adhesion molecules (CAMs) on brain ECs and release cytokines and chemokines simultaneously (4). Activated CD8+ T cells express CXCR3 and CCR5 chemokine receptors, which bind to chemokines such as CXCL9, CXCL10, and CXCL4, inducing T-cell migration to the brain (5). Meanwhile, LFA-1 on CD8+ T cells promotes their adhesion to endothelial ICAM-1 (6). Parasitic antigens can be transferred from the vascular lumen to brain ECs. Brain ECs can cross-present parasitic antigens on MHC-1 molecular antigens and bind with antigen receptors (TCRs) on CD8+ T cells (7). The interaction induces apoptosis of ECs, leading to the destruction of the BBB (8). Meanwhile, the iRBCs directly activate platelets and stimulate the release of CXCL4. CXCL4 induces the production of TNF by T cells and macrophages, which causes more platelets to adhere to ECs (9). As leukocytes and platelets are recruited and activated, a local proinflammatory cycle ensues, with a positive feedback loop of EC activation, leukocyte/platelet sequestration, and parasite accumulation (10).
Molecular mechanisms of blood–brain barrier dysfunction. The binding of P. falciparum erythrocyte membrane protein-1 (PfEMP-1) to the receptors on the ECs, including ICAM-1, VCAM-1, and EPCR, may trigger multiple signaling pathways in ECs, leading to the change to cytoskeleton-associated proteins, ultimately resulting in the disruption of the BBB. Meanwhile, signaling pathways triggered by PfEMP1 lead to activation and injury of astrocytes, microglia, neurons, and perivascular macrophages and initiate the process of neuropathological injury. The binding of PfEMP1 to EPCR fosters the activation of tissue factors Va and VIIIa, thereby disrupting the anticoagulant pathway. Activation of these tissue factors results in thrombin generation, leading to fibrin deposition. Microglia also disrupt the BBB by producing TNF and IL-1β. Astrocytes retract their end feet from ECs, resulting in reduced vascular wrapping. Angiopoietin-2 produced by ECs also leads to reduced vascular wrapping by inducing pericyte dysfunction. The iRBCs stimulate leukocytes to release inflammatory cytokines (TNF-α, IL-1α, IL-1β) by releasing parasitic toxins. These cytokines disrupt BBB integrity by altering tight junctions and activating ECs to release chemokines (CCL2, CCL4, CXCL4, CXCL8, and CXCL10), which promote leukocyte accumulation, including CD4+ T cells and CD8+ T cells. Infiltrated leukocytes induce EC apoptosis through granzyme B and perforin-mediated cytotoxicity. Granzyme B and perforin directly induce neuronal cell death. Adhesion of iRBCs, leukocytes, and platelets to ECs also causes EC damage and irreversible changes. Due to the increased permeability of the BBB, cytokines, chemokines, immune cells, and plasma factors flood into the brain parenchyma and activate neurons and astrocytes, resulting in nerve injury and neurological sequelae. Kynurenic acid produced by macrophages and ECs during tryptophan metabolism is further converted into cytotoxic quinoline, which plays a vital role in stromal cells and microglia. These molecules induce the disruption of the BBB.
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