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A primate model for human cerebral malaria: Plasmodium coatneyi-infected rhesus monkeys
1Institute of Pathology, Case Western Reserve University, Cleveland, Ohio.
Abstract:
A major factor in the pathogenesis of human cerebral malaria is blockage of cerebral microvessels by the sequestration of parasitized human red blood cells (PRBC). In vitro studies indicate that sequestration of PRBC in the microvessels is mediated by the attachment of knobs on PRBC to receptors on the endothelial cell surface such as CD36, thrombospondin (TSP), and intercellular adhesion molecule-1 (ICAM-1). However, it is difficult to test this theory in vivo because fresh human brain tissues from cerebral malarial autopsy cases are not easy to obtain. Although several animal models for human cerebral malaria have been proposed, none have shown pathologic findings that are similar to those seen in humans. In order to develop an animal model for human cerebral malaria, we studied brains of rhesus monkeys infected with the primate malaria parasite, Plasmodium coatneyi. Our study demonstrated PRBC sequestration and cytoadherence of knobs on PRBC to endothelial cells in the cerebral microvessels of these monkeys. Cerebral microvessels with sequestered PRBC were shown by immunohistochemical analysis to possess CD36, TSP, and ICAM-1. These proteins were not evident in the cerebral microvessels of uninfected control monkeys. Thus, our study indicates, for the first time, that rhesus monkeys infected with P. coatneyi can be used as a primate model to study human cerebral malaria. By using this animal model, we may be able to evaluate strategies for the development of vaccines to prevent human cerebral malaria.
Insights
Rhesus monkeys infected with Plasmodium coatneyi provide a new primate model for studying human cerebral malaria. This model shows parasitized red blood cell sequestration and adhesion in cerebral microvessels, aiding research into malaria pathogenesis and prevention.
Area of Science:
- Pathology
- Immunology
- Parasitology
Background:
- Cerebral malaria pathogenesis involves microvessel blockage by parasitized red blood cells (PRBC).
- In vitro studies suggest PRBC sequestration is mediated by knob protein interactions with endothelial receptors like CD36, TSP, and ICAM-1.
- Existing animal models do not fully replicate human cerebral malaria pathology.
Purpose of the Study:
- To develop and validate a new primate model for human cerebral malaria.
- To investigate the in vivo mechanisms of PRBC sequestration in cerebral microvessels.
- To assess the expression of key adhesion molecules in a relevant animal model.
Main Methods:
- Infection of rhesus monkeys with Plasmodium coatneyi.
- Analysis of cerebral microvessels for PRBC sequestration and cytoadherence.
- Immunohistochemical analysis of CD36, TSP, and ICAM-1 expression in cerebral microvessels.
Main Results:
- Demonstrated PRBC sequestration and knob cytoadherence in cerebral microvessels of infected rhesus monkeys.
- Confirmed the presence of CD36, TSP, and ICAM-1 in cerebral microvessels with sequestered PRBC.
- Observed absence of these proteins in cerebral microvessels of uninfected control monkeys.
Conclusions:
- Rhesus monkeys infected with P. coatneyi represent a valid primate model for human cerebral malaria.
- This model allows in vivo study of PRBC sequestration and adhesion mechanisms.
- The model can be utilized to evaluate strategies for cerebral malaria prevention, including vaccine development.