Pathophysiology of Blood-Brain Barrier Disruption in Cerebral Malaria and Distant Organ Involvement

Cerebral malaria is a life-threatening complication of malarial disease caused by the parasite Plasmodium falciparum, with children being the most affected population. It is responsible for approximately 90% of malaria deaths, and around 25% of patients who survive suffer from long-term neurological problems, including seizures and neurocognitive deficits that profoundly affect their quality of life. The symptoms and signs of cerebral malaria are diverse in adults and children, ranging from fever, headache, and irritability to agitation, delirium, seizures, vomiting, and coma. The pathophysiology is also complex and age-dependent, involving sequestration of infected erythrocytes, cerebral inflammation, dysregulation of coagulation, and endothelial dysfunction. The essential role of the blood-brain barrier (BBB) in this process is well known, but the precise underlying mechanisms of BBB disruption during cerebral malaria remain unclear. Studies in humans and mouse models have discovered several nonexclusive pathogenic mechanisms associated with disturbances of the BBB after parasite infection: adhesion of infected red blood cells, release of pro-inflammatory cytokines, and cerebrovascular constriction due to increased blood coagulation in the microvasculature. Moreover, activation of astrocytes and microglia has also been proposed to play a role through the regulation of cytokines and chemokines. Pericyte dysfunction has also been reported in cerebral malaria, pointing towards their role in maintaining the integrity of the BBB. A role for extracellular vesicles, notably microparticles, abnormal accumulation of metabolites, and microRNAs has also been proposed. Finally, recent reports have highlighted the effects of distant organ dysfunction on the brain in severe malaria, which has challenged our understanding of the concept of “cerebral” malaria. The BBB and gut barrier communicate with each other and with the environment through a complex network of interactions that may exacerbate microvascular lesions in cerebral malaria. Similarly, renal impairment has been associated with more severe brain damage in falciparum malaria through a variety of pathogenic processes. No specific or adjunctive treatment exists to treat cerebral malaria to date, so understanding the mechanisms involved in the disturbance of BBB integrity will facilitate the discovery of new therapeutic targets.

This Research Topic aims to collect the most recent knowledge about the mechanisms responsible for the breakdown of the BBB in cerebral malaria, with a wider focus on the role of distant organ involvement in severe falciparum infection, including liver, kidney, lung, and gut dysfunction. We welcome all types of manuscripts (original research, review, minireviews, methods, and perspectives) and encourage submissions covering, but not limited to, the following themes.

To gather further insights into the complex interactions and mechanisms underlying cerebral and non-cerebral pathology in severe malaria, we welcome articles addressing, but not limited to, the following themes:

- New experimental models to study the disruption/remodelling of the BBB in cerebral malaria, such as organ-on-a-chip, organoid techniques, etc.
- Immune responses to malaria at the BBB
- BBB integrity in patients with long-term neurological conditions and the role of distant organ dysfunction
- Biomarkers of BBB disruption and novel diagnostic/prognostic tools
- Repair mechanisms in survivors and injury-reversal therapeutic strategies

Keywords: Cerebral malaria, pathogenesis, blood brain barrier (BBB), neurological deficits, therapeutic strategies

Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.