Non-human primate models of malarial anemia

这项建议的广泛的长期目标是了解贫血引起的机制基础， 疟原虫为了实现这一目标，我们将开发Macaca mulatto（恒河猴）和Aotusnon- 人类灵长类动物实验模型系统，以解决眼前的问题以及假设， 在这个项目的过程中发展。非人灵长类动物的疟疾性贫血表现出特征性 这与在感染疟原虫的患者中观察到的贫血非常相似，同样， 急性和慢性感染，并取决于宿主的免疫状态。食蟹猴疟原虫 P. Coatmyi感染M.黑白混血猴的疟疾感染与间日疟原虫引起的人类疟疾感染相当 和恶性疟原虫，并且类似地，可导致中度和重度贫血的发展。 恒河猴模型的开发将允许最深入地研究 疟疾性贫血，定量评估正常红细胞过早破坏的程度 细胞、无效红细胞生成和红细胞生成不良是主要因素。细胞因子和其他 还将研究免疫致病因素。另一方面， 目前，这是疟疾疫苗测试的重要模型。慢性中度至低度或 在这些动物中观察到亚显性寄生虫血症， 贫血，这是知之甚少。拟议研究的具体目标是：1）建立和 严格评估临床、血液学、寄生虫学和免疫学的动态测量 确定恒河猴疟疾性贫血分子机制基础的参数 实验感染了Coatneyi疟原虫和食蟹猴疟原虫; 人，分别;和2）检查和比较疟疾贫血的机制基础，观察到在 实验接种的南西猴暴露于同源攻击， 用恶性疟原虫进行异源再攻击。

The broad long-term objective of this proposal is to understand the mechanistic basis of anemia caused by Plasmodium. To reach this objective, we will develop Macaca mulatto (rhesus macaque) and Aotusnon- human primate experimental model systems to address immediate questions as well as hypotheses that develop in the course of this project. Malarial anemia in non-human primates manifests with characteristics that are very similar to anemia observed in patients infected with Plasmodium, and,similarly, differs with acute and chronic infections and depending upon the immune status of the host. Plasmodium cynomolgi and P. coatmyi infections in M. mulatto monkeys are comparable to human malaria infections caused by P. vivax and P. falciparum, respectively, and,similarly, can result in the development of moderate and severe anemia. The development of the rhesus monkey model will allow the most in depth study of the underlying basis of malarial anemia, to quantitatively assess the degree to which the premature destruction of normal red blood cells, ineffective erythropoiesis, and dyserythropoiesis are major factors. The roles of cytokines and other immunopathogenic factors will also be investigated. P. falciparum infections of Aotus monkeys, on the other hand, are currently important models for the testing of malaria vaccines. Chronic moderate to low-level or sub-patent parasitemias are observed in these animals with frequent but varied degrees of moderate to severe anemia, which is poorly understood. The specific aims of the proposed studies are to 1) establish and rigorously evaluate kinetic measurements of clinical, hematological, parasitological, and immunological parameters to determine the molecular mechanistic basis of malarial anemia in rhesus macaque monkeys experimentally infected with P. coatneyi and P. cynomolgi; models for P. falciparum and P. vivax infection in humans, respectively; and 2) examine and compare the mechanistic basis of malarial anemia observed in experimentally vaccinated Aotus nancymai monkeys that are exposed to homologous challenge and heterologous re-challenge with P. falciparum.