Transcellular blood-brain barrier disruption in malaria-induced reversible brain edema.

Jessica Jin,Sabine Heiland,Friedrich Frischknecht,Rajyabardhan Pattnaik,Manuel Fischer,Sanjib Mohanty,Angelika Hoffmann,Lukas Pirpamer,Chi Ho Wai,Samuel C Wassmer,Johannes Pfeil,Michael Lanzer,Praveen K Sahu,Martin Bendszus,Megharay Majhi,Mame Aida Ba,Ann-Kristin Mueller,Marek Cyrklaff

doi:10.26508/lsa.202201402

Abstract

Brain swelling occurs in cerebral malaria (CM) and may either reverse or result in fatal outcome. It is currently unknown how brain swelling in CM reverses, as brain swelling at the acute stage is difficult to study in humans and animal models with reliable induction of reversible edema are not known. In this study, we show that reversible brain swelling in experimental murine CM can be induced reliably after single vaccination with radiation-attenuated sporozoites as proven by in vivo high-field magnetic resonance imaging. Our results provide evidence that brain swelling results from transcellular blood-brain barrier disruption (BBBD), as revealed by electron microscopy. This mechanism enables reversal of brain swelling but does not prevent persistent focal brain damage, evidenced by microhemorrhages, in areas of most severe BBBD. In adult CM patients magnetic resonance imaging demonstrate microhemorrhages in more than one third of patients with reversible edema, emphasizing similarities of the experimental model and human disease. Our data suggest that targeting transcellular BBBD may represent a promising adjunct therapeutic approach to reduce edema and may improve neurological outcome.

Highlights

Cerebral malaria (CM) is the most severe complication of Plasmodium falciparum infection
To test whether the experimental cerebral malaria (ECM) model associates with reversible brain swelling, we performed serial magnetic resonance imaging (MRI) on C57Bl/6 mice infected with a low number (1,000) of Plasmodium berghei (Pb ANKA) sporozoites
It is noteworthy that similar MRI findings have been demonstrated in 55% of P. berghei ANKA (Pb ANKA)–infected mice treated with a glutamine antagonist [13]

Summary

Introduction

Cerebral malaria (CM) is the most severe complication of Plasmodium falciparum infection. It is characterized by altered consciousness and coma, and by brain swelling in children and, to a lesser degree, in adults. A report on stroke [9], which is associated with reversible brain edema, suggests a transcellular BBBD as the main mechanism of early edema formation in stroke. It remains unclear whether transcellular BBBD occurs in other diseases with reversible brain swelling, and which factors determine the reversibility of brain swelling

Methods

Results

Conclusion