Non-human primate models of malarial anemia

这项提议的广泛的长期目标是了解由以下原因引起的贫血的机制 疟原虫。为了达到这一目标，我们将培育猕猴(恒河猴)和奥特松- 人类灵长类实验模型系统，用于解决眼前的问题和假设 在这个项目的过程中发展。非人灵长类疟疾贫血的特点 这些疾病与感染疟原虫的患者中观察到的贫血非常相似，同样，与 急性和慢性感染，取决于宿主的免疫状态。食蟹猴疟原虫和食蟹猴疟原虫 毛猴的衣原体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，同样可导致中度和重度贫血。 恒河猴模型的发展将使我们能够最深入地研究 疟疾贫血，以定量评估正常红细胞过早破坏的程度 细胞、无效的红细胞生成和红细胞生成障碍是主要因素。细胞因子和其他因子的作用 免疫致病因素也将被调查。另一方面，恶性疟原虫对Aotus猕猴的感染 目前，它们是测试疟疾疫苗的重要模型。慢性中至低水平或 在这些动物中观察到亚专利寄生虫病，但有不同程度的中度到重度 贫血，人们对此知之甚少。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 确定恒河猴疟疾贫血分子机制基础的参数 实验感染科氏疟原虫和食蟹猴疟原虫；恶性疟原虫和间日疟原虫感染模型 以及2)检查和比较观察到的疟疾贫血的机制基础 实验接种了暴露于同源挑战和 异源恶性疟原虫的再挑战。

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.