Plasmodium falciparum infection of the humanized NOD/SCID/IL2r[gamma][null] mouse

描述（由申请人提供）：疟疾每年造成100多万儿童死亡，其中大多数死亡可归因于恶性疟原虫。然而，尽管经过多年的深入研究，对抗恶性疟疾的有效疫苗仍然难以捉摸。人类疟疾的小动物模型将极大地促进我们对人类对疟疾的免疫反应的理解，并为筛选这种急需的疫苗提供一个现成的模型。该提案的目标是开发一种人源化的疟疾小鼠模型。为了实现这一目标，我们将在两种潜在的人源化小鼠模型中进行选择，这些小鼠模型重建了人类适应性免疫系统，并循环了作为恶性疟原虫复制靶点的人类红细胞。待测试的两种人源化小鼠模型是：（1）将人脐带血干细胞静脉内移植到经辐照的新生NOD/scidltz/IL 2 R3裸小鼠中，和（2）将胎儿人胸腺和肝组织移植到经辐照的成年NOD/scidltz/IL 2 R3裸小鼠的肾包膜下，随后静脉内注射同源肝干（CD 34+）细胞。最近的研究结果表明，人CD 45+白细胞和人血型糖蛋白A+红细胞在移植小鼠的血液中很容易检测到，表明这些模型可能：（1）支持恶性疟原虫复制，和（2）引发可测量的人细胞和抗体介导的对恶性疟原虫的免疫应答。为了比较这两种恶性疟原虫疟疾的人源化小鼠模型，我们将分析恶性疟原虫寄生虫血症的程度、时间过程和结果，并将寄生虫血症与发展中的人类免疫应答联系起来。这项研究的结果将建立一个人源化的小鼠模型，为识别免疫系统对血液阶段感染的保护性成分提供新的机会。这些研究的结果将有助于靶向机制，细胞和/或人类免疫系统的分子，用于未来的疟疾疫苗设计。 项目简介：该项目的目标是开发一种人源化的疟疾小鼠模型。拟议研究的结果将提供新的机会，以确定免疫系统对血液阶段感染的保护性成分，然后针对人类免疫系统的机制，细胞和/或分子，用于未来的疟疾疫苗设计。

DESCRIPTION (provided by applicant): Malaria kills more than 1 million children annually with most deaths attributable to Plasmodium falciparum. Yet despite years of intensive research, an efficacious vaccine against falciparum malaria remains elusive. A small animal model of human malaria would greatly enhance progress toward our understanding of the human immune response to malaria, as well as providing a readily available model for screening this much needed vaccine. The goal of this proposal is to develop a humanized mouse model of malaria. To achieve this, we will select between two potential humanized mouse models that reconstitute the human adaptive immune system, as well as circulate human erythrocytes that are targets for the replication of P. falciparum. The two humanized mouse models to be tested are: (1) human cord blood stem cells transplanted intravenously into irradiated neonatal NOD/scidltz/IL2R3null mice and (2) fetal human thymus and liver tissue engrafted under the renal capsule of irradiated adult NOD/scidltz/IL2R3null mice followed by the intravenous injection of homologous liver stem (CD34+) cells. Recent findings indicate that human CD45+ leukocytes and human glycophorin A+ erythrocytes are readily detectable in the blood of the engrafted mice, indicating that these models will likely: (1) support P. falciparum replication, and (2) elicit measurable human cell- and antibody-mediated immune responses to P. falciparum. To compare these two humanized mouse models of P. falciparum malaria, we will analyze the magnitude, time course and outcome of P. falciparum parasitemia and relate parasitemia to the developing human immune responses. The results of the proposed research will establish a humanized mouse model that will provide new opportunities to identify protective components of the immune system responding to blood-stage infection. The results of these studies will help to target mechanisms, cells, and/or molecules of the human immune system for future malaria vaccine design. PROJECT NARRATIVE: The goal of this proposal is to develop a humanized mouse model of malaria. The results of the proposed research will provide new opportunities to identify protective components of the immune system responding to blood-stage infection, and then target mechanisms, cells, and/or molecules of the human immune system for future malaria vaccine design.