Molecular mechanisms in pediatric cerebral malaria pathogenesis and Immunity
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Date
2021-07-21
Authors
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Publisher
Kamuzu University of Health Sciences
Abstract
Type of Research Study: Prospective case control study
Problem: Malaria, caused by the parasite P. falciparum, remains a significant public health
problem in Malawi.
Objectives: We plan to 1) determine which subset of parasites are responsible for binding to
the microvessels of the brain and gut, and 2) investigate the role of lactate in altering the binding
characteristics of parasitized erythrocytes to microvessels.
Methodology: We have devised a novel 3D microvessel model that accurately mimics the flow
velocity and wall shear stress present in the microvessels of the brain. We are able to create an
in vitro model of the human brain microcirculation by forming very small 3D blood microvessels
from primary human brain endothelial cells, thus accurately mimicking both the cellular and
fluidic environment that a parasitized erythrocyte would encounter in the brain. We will use this
3D human brain microvessel model, as well as characterized parasites from malaria patients to
investigate the receptors and milieu contributing to life-threatening cerebral malaria infections.
Expected findings and dissemination: We anticipate finding a subset of parasites, those
expressing a certain subset of PfEMP1 molecules on their surface, that are most adept at
binding to brain endothelial cells. We anticipate that the innovative 3D microvessel model will
elucidate parasite binding differences under certain flow-based, shear stresses that have not
previously been appreciated, given previous models were unable to mimic physiologic flow and
the curvature of a blood vessel wall. We also anticipate being able to use this unique model, in
combination with known antibodies and shRNA techniques to determine the role of various
proteins on the endothelial cell surface in mediating this binding. Moreover, we will determine if
different subsets of parasites will adhere to brain and gut microvessels, which are the
predominant organs of parasite accumulation in deadly malaria infections. Finally, we will be
able to use this model to evaluate the role of external molecules, such as lactate, on infected
erythrocyte binding in a physiologically relevant model system.
Results will be disseminated in peer-reviewed journals, international conferences, the University
of Malawi College of Medicine Research Dissemination Conference, and will be provided to
COMREC and community leaders.