A Primate Model for Human Cerebral Malaria: Plasmodium coatneyi-Infected Rhesus Monkeys

Masamichi AikawaInstitute of Pathology, Case Western Reserve University, Armed Forces Research Institute of Medical Sciences, DNAX Research Institute of Molecular and Cellular Biology, Malaria Branch, Center for Infectious Diseases, Centers for Disease Control, Cleveland, Ohio, Thailand

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Arthur BrownInstitute of Pathology, Case Western Reserve University, Armed Forces Research Institute of Medical Sciences, DNAX Research Institute of Molecular and Cellular Biology, Malaria Branch, Center for Infectious Diseases, Centers for Disease Control, Cleveland, Ohio, Thailand

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C. Dahlem SmithInstitute of Pathology, Case Western Reserve University, Armed Forces Research Institute of Medical Sciences, DNAX Research Institute of Molecular and Cellular Biology, Malaria Branch, Center for Infectious Diseases, Centers for Disease Control, Cleveland, Ohio, Thailand

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Tatsuya TegoshiInstitute of Pathology, Case Western Reserve University, Armed Forces Research Institute of Medical Sciences, DNAX Research Institute of Molecular and Cellular Biology, Malaria Branch, Center for Infectious Diseases, Centers for Disease Control, Cleveland, Ohio, Thailand

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Russell J. HowardInstitute of Pathology, Case Western Reserve University, Armed Forces Research Institute of Medical Sciences, DNAX Research Institute of Molecular and Cellular Biology, Malaria Branch, Center for Infectious Diseases, Centers for Disease Control, Cleveland, Ohio, Thailand

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Thomas H. HaslerInstitute of Pathology, Case Western Reserve University, Armed Forces Research Institute of Medical Sciences, DNAX Research Institute of Molecular and Cellular Biology, Malaria Branch, Center for Infectious Diseases, Centers for Disease Control, Cleveland, Ohio, Thailand

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Yoshihiro ItoInstitute of Pathology, Case Western Reserve University, Armed Forces Research Institute of Medical Sciences, DNAX Research Institute of Molecular and Cellular Biology, Malaria Branch, Center for Infectious Diseases, Centers for Disease Control, Cleveland, Ohio, Thailand

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George PerryInstitute of Pathology, Case Western Reserve University, Armed Forces Research Institute of Medical Sciences, DNAX Research Institute of Molecular and Cellular Biology, Malaria Branch, Center for Infectious Diseases, Centers for Disease Control, Cleveland, Ohio, Thailand

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William E. CollinsInstitute of Pathology, Case Western Reserve University, Armed Forces Research Institute of Medical Sciences, DNAX Research Institute of Molecular and Cellular Biology, Malaria Branch, Center for Infectious Diseases, Centers for Disease Control, Cleveland, Ohio, Thailand

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Kyle WebsterInstitute of Pathology, Case Western Reserve University, Armed Forces Research Institute of Medical Sciences, DNAX Research Institute of Molecular and Cellular Biology, Malaria Branch, Center for Infectious Diseases, Centers for Disease Control, Cleveland, Ohio, Thailand

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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.

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