Abstract
Malaria, the most prevalent mosquito-borne infectious disease worldwide, has accompanied humanity for millennia and remains an important public health issue despite advances in its prevention and treatment. Most infections are asymptomatic, but a small percentage of individuals with a heavy parasite burden develop severe malaria, a group of clinical syndromes attributable to organ dysfunction. Cerebral malaria is an infrequent but life-threatening complication of severe malaria that presents as an acute cerebrovascular encephalopathy characterized by unarousable coma. Despite effective antiparasite drug treatment, 20% of patients with cerebral malaria die from this disease, and many survivors of cerebral malaria have neurocognitive impairment. Thus, an important unmet clinical need is to rapidly identify people with malaria who are at risk of developing cerebral malaria and to develop preventive, adjunctive and neuroprotective treatments for cerebral malaria. This Review describes important advances in the understanding of cerebral malaria over the past two decades and discusses how these mechanistic insights could be translated into new therapies.
Key points
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Cerebral malaria is an acute, life-threatening cerebrovascular complication characterized by unarousable coma; children <5 years are most at risk, although cerebral malaria can develop at any age.
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Effective treatments for blood-stage malaria include antiparasite drugs such as artesunates and therapies that increase pitting, opsonization and phagocytic clearance of infected erythrocytes.
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Host–parasite interactions result in sequestration of infected erythrocytes and immune cells on brain endothelial cells, which can lead to vascular disintegration, disruption of the blood–brain barrier and potentially neuropathology.
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CD8+ T cell-mediated immune responses during cerebral malaria contribute to endothelial injury and blood–brain barrier disintegration, highlighting potential roles for therapies that target T cell recruitment, activation and cytotoxicity.
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Host–parasite interactions result in the activation of microglia and astrocytes; thus, manipulation of these brain-resident cells might beneficially influence the neuropathology of cerebral malaria.
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Cerebral malaria can be alleviated by combinations of therapies that clear infected cells and parasites, ideally complemented in the future by therapies that increase the resilience of the brain to tissue damage.
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Change history
06 November 2023
A Correction to this paper has been published: https://doi.org/10.1038/s41582-023-00899-8
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Acknowledgements
A.H. was supported by an MD/PhD stipend (TI 07.001_Hadjilaou) and is currently supported by a Clinical Leave stipend of the Bundesministerium für Bildung und Forschung/Deutsches Zentrum für Infektionsforschung (TI 07.002_Hadjilaou).
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A.H. outlined the content of the manuscript, wrote the first draft of the manuscript and figures and researched data for the article. All authors contributed substantially to discussions of the article content, reviewed and/or edited the manuscript and figures before submission.
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Glossary
- Anaphylatoxins
-
Potent, low-molecular-weight molecules produced during immune responses that stimulate inflammation, attract white blood cells and modulate immune responses to infection or disease.
- Efferocytosis
-
The clearance of damaged cells by phagocytosis.
- Glymphatic system
-
A paravascular system thought to be responsible for waste clearance in the central nervous system, similar to the lymphatic system in other organs.
- Howell–Jolly bodies
-
Small, round, basophilic, nuclear remnants of DNA within mature erythrocytes, which are typically removed in the spleen through a process called ‘pitting’.
- Immunoproteasomes
-
Proteasomes in the cytoplasm of immune cells, especially antigen-presenting ones, formation of which is induced by pro-inflammatory cytokines or oxidative stress.
- Malarial retinopathy
-
A collection of changes in the retina that can occur during Plasmodium infection.
- Metabolic reprogramming
-
Cellular metabolic changes that address increased bioenergetic and biosynthetic demands, such as those needed in the transition from a quiescent to an activated phenotype.
- Opsonization
-
The process by which circulating, soluble proteins (opsonins) bind to a cell membrane, thereby marking those cells for phagocytosis.
- Prenylation
-
A chemical modification that enables anchoring of a protein to the cell membrane.
- Reticulocytes
-
Immature erythrocytes characterized by a reticular network of ribosomal RNA.
- Rosetting
-
The increased cytoadhesion of erythrocytes infected with mature, asexual Plasmodium falciparum causes these cells to stick to uninfected erythrocytes, forming flower-like cell clusters.
- Sequestration
-
The cytoadherence of Plasmodium-infected erythrocytes to the vascular endothelium, a feature predominantly seen in Plasmodium falciparum infections.
- S-nitrosylation
-
A post-translational peptide modification in which a nitrosyl group is added to the sulfur atom of a cysteine residue.
- Statins
-
3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors approved for the treatment of hypercholesterolaemia.
- Transmission intensity
-
A measure of the frequency of malaria spread in a specific area, which is dictated by mosquito population density, local climate conditions and the level of human immunity (which shapes individual exposure to malaria antigens and the development of protective immunity).
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Hadjilaou, A., Brandi, J., Riehn, M. et al. Pathogenetic mechanisms and treatment targets in cerebral malaria. Nat Rev Neurol 19, 688–709 (2023). https://doi.org/10.1038/s41582-023-00881-4
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DOI: https://doi.org/10.1038/s41582-023-00881-4
