Understanding Molecular Mechanisms of Vascular Dysfunction in Malaria
Using in vitro models and clinical cohorts to understand vascular aspects of disease and investigate interventions to restore vascular function.
During the blood stage of malaria caused by Plasmodium falciparum, red blood cells infected with the parasite may sequester in blood vessels by binding to their endothelial lining. Sequestration protects the parasites from splenic clearance mechanisms and can trigger severe complications including cerebral malaria, in which infected blood cells adhere to brain microvessels.
A major focus of the Smith lab is deciphering how infected red blood cells attach to microvessels and how this contributes to malaria pathogenesis. Parasite sequestration in microvessels is mediated by binding of P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) to human endothelial protein C receptor (EPCR). Involvement of EPCR explains how sequestration may increase the severity of malaria: EPCR is involved in coagulation, inflammation, and the protective barrier functions of the endothelium, all of which may be disrupted by binding of infected red blood cells. However, cerebral malaria research has been hampered by the inaccessibility of the brain and the lack of appropriate in vitro models.
The Smith lab collaborates with researchers in Africa and India to investigate molecular mechanisms in severe malaria. For example, Dr. Smith’s group is working in collaboration with Dr. Zheng’s lab in the Department of Bioengineering at the University of Washington and a clinical research team from Michigan State University and the Blantrye Malaria Project to study parasite isolates from cerebral malaria patients in novel 3D human brain microvessel models. The Smith lab has identified biomarkers of severe disease in adults and published evidence that suggests that malaria treatments that prevent PfEMP1-EPCR interaction or that restore EPCR function may be effective. Following up on this observation, the Smith lab collaborates with Dr. Alexis Kaushansky’s group at the Center for Global Infectious Disease Research in investigating how kinase signaling pathways are involved in endothelial barrier properties and studying new host-directed therapeutic approaches to strengthen the blood-brain barrier.
Dr. Smith is interested in partnerships that can translate his laboratory’s findings about P. falciparum interactions with host endothelial proteins adjunct treatments for severe malaria and new approaches to treat vascular dysfunction from infectious or non-infectious disease. The Smith group has an in vitro blood-brain-barrier model that they are using in collaborations to identify potential malaria treatments, including screening drug compounds. This work has broader implications, for example in finding ways to control the permeability of the blood-brain barrier.
Stage of Development
- Preclinical in vitro
- Preclinical drug discovery
- Collaborative research opportunity
- Sponsored research agreement
- Consultation agreement
- In vitro model
- Drug screening in other disease models
- Glennon, E.K.K., Dankwa S., Smith J.D., and Kaushansky A. Opportunities for host-targeted therapies for malaria. Trends in Parasitology. 2018. 34:843-860. PMCID:PMC6168423.
- Bernabeu M, Gunnarsson C, Vishnyakova M, Howard CC, Nagao RJ, Avril M...Smith JD. Binding heterogeneity of falciparum to 3D brain microvessels is mediated by EPCR and ICAM-1. mBio 2019. May 28;10(3). pii: e00420-19. doi:10.1128/mBio.00420-19.
- Kessler A, Dankwa S, Bernabeu M, Harawa V, Danziger SA... Smith JD... Linking EPCR-Binding PfEMP1 to brain swelling in pediatric cerebral malaria. Cell Host Microbe. 2017;22(5):601-614.
- Bernabeu M, Danziger SA, Avril M, Vaz M, Babar PH, Brazier AJ...Smith JD. Severe adult malaria is associated with specific PfEMP1 adhesion types and high parasite biomass. PNAS. 2016;113(23):E3270-E3279.