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Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria
Anne Kessler1, Selasi Dankwa2, Maria Bernabeu2
1Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY 10461, USA.
Abstract:
Brain swelling is a major predictor of mortality in pediatric cerebral malaria (CM). However, the mechanisms leading to swelling remain poorly defined. Here, we combined neuroimaging, parasite transcript profiling, and laboratory blood profiles to develop machine-learning models of malarial retinopathy and brain swelling. We found that parasite var transcripts encoding endothelial protein C receptor (EPCR)-binding domains, in combination with high parasite biomass and low platelet levels, are strong indicators of CM cases with malarial retinopathy. Swelling cases presented low platelet levels and increased transcript abundance of parasite PfEMP1 DC8 and group A EPCR-binding domains. Remarkably, the dominant transcript in 50% of swelling cases encoded PfEMP1 group A CIDRα1.7 domains. Furthermore, a recombinant CIDRα1.7 domain from a pediatric CM brain autopsy inhibited the barrier-protective properties of EPCR in human brain endothelial cells in vitro. Together, these findings suggest a detrimental role for EPCR-binding CIDRα1 domains in brain swelling.
Insights
Brain swelling in pediatric cerebral malaria (CM) is linked to specific parasite proteins. These proteins, particularly EPCR-binding domains, disrupt brain endothelial cells, suggesting a key role in CM-related brain swelling and mortality.
Area of Science:
- Infectious Diseases
- Neuroscience
- Genetics
Background:
- Brain swelling is a critical factor in pediatric cerebral malaria (CM) mortality.
- The precise mechanisms driving brain swelling in CM are not fully understood.
Purpose of the Study:
- To investigate the molecular mechanisms underlying brain swelling in pediatric cerebral malaria.
- To develop machine-learning models for predicting malarial retinopathy and brain swelling.
Main Methods:
- Combined neuroimaging, parasite transcript profiling, and blood biomarker analysis.
- Developed machine-learning models to identify indicators of CM complications.
- Utilized in vitro assays with recombinant parasite domains and human brain endothelial cells.
Main Results:
- Specific parasite var transcripts (EPCR-binding domains), high parasite biomass, and low platelets indicate malarial retinopathy.
- Low platelets and increased abundance of PfEMP1 DC8 and group A EPCR-binding domains are associated with brain swelling.
- A recombinant CIDRα1.7 domain from PfEMP1 inhibited endothelial protein C receptor (EPCR) barrier function in vitro.
Conclusions:
- Parasite EPCR-binding CIDRα1 domains play a detrimental role in CM-induced brain swelling.
- These findings highlight potential therapeutic targets for reducing CM-related brain swelling.
