Suppression of Erythropoiesis in Malaria Infection

描述（由申请人提供）：拟定的研究旨在确定巨噬细胞抑制因子（MIF）的高表达等位基因是否与严重疟疾性贫血的发生相关，并描述MIF在疟疾背景下抑制红细胞生成的机制。恶性疟原虫感染每年导致100万至200万人死亡，其中大多数是五岁以下的非洲儿童。死亡发生于感染并发症，包括严重和难治性贫血。最近在灵长类动物中开发疟疾疫苗的尝试也受到了接种疫苗和挑战感染后严重贫血的阻碍。这些贫血的病理生理学尚不清楚。我们已经发现，MIF在许多疟疾感染的个体中高水平表达，抑制红系祖细胞发育，并拮抗促红细胞生成素信号传导。因此，MiF的作用反映了许多严重疟疾贫血患者的临床分析。本申请的目的是鉴定MIF高表达的发病基础和MIF干扰红系祖细胞发育的机制。中心假设是，严重的疟疾贫血是由于遗传易感性过度生产的MIF加上MIF的能力，以抑制红细胞生成诱导持续激活的ERK-1/2 MAP激酶级联反应。我们已经制定了这一假设的基础上，我们的实验研究表明，第一，MIF是在疟疾感染期间的血液和骨髓中表达，第二，存在的多态性内的Mifgene的启动子，影响其表达水平和第三，MIF抑制红系祖细胞的发展。所提出的研究的具体目的是：1）确定重度疟疾贫血患者和适当对照中低表达（5-CATT）和高表达（6-、7-、8-CATT）Mif等位基因的频率，并确定高表达等位基因是否与重度贫血相关，以及2）确定负责疟疾感染期间抑制红细胞生成的途径。我们希望建立，有过度代表性的高表达在严重的疟疾性贫血患者，并确定MIF维持ERK-1/2激活和干扰促红细胞生成素的作用的细胞内机制。这些结果将是重要的，因为它们将提供一个更精确的理解的分子途径负责严重疟疾贫血。

DESCRIPTION (provided by the applicant): The proposed research is designed to determine if high expression alleles of macrophage inhibitory factor (MIF) are associated with the development of severe malarial anemia, and to characterize the mechanism whereby MIF suppresses erythropoiesis in the setting of malaria. Infection by P. falciparum results in 1-2 million deaths a year, mostly in African children under the age of five. Death occurs from the complications of infection, which include a severe and refractory anemia. Recent attempts to develop a malaria vaccine in primates also have been hampered by severe anemia after vaccination and challenge infection. The pathophysiology of these anemias is unknown. We have discovered that MIF is expressed in high levels in many malaria-infected individuals, suppresses erythroid progenitor development, and antagonizes erythropoietin signaling. MiF's action thus reflects the clinical analysis of many patients with severe malarial anemia. The objective of this application is to identify the pathogenetic basis for high MIF expression and the mechanism by which MIF interferes with the development of erythroid progenitor cells. The central hypothesis is that severe malarial anemia is the result of genetic predisposition to overproduction of MIF coupled with MIF's capacity to suppress erythropoiesis by inducing sustained activation of the ERK-1/2 MAP kinase cascade. We have formulated this hypothesis on the basis of our experimental studies showing first, that MIF is expressed in the blood and bone marrow during malaria infection, second, that there exists a polymorphism within the promoter of the Mifgene that affects its level of expression and third, that MIF inhibits erythroid progenitor development. The specific aims of the proposed research are: 1) Define the Frequency of Low Expression (5-CATT) and High Expression (6-, 7-, 8-CATT) Mif Alleles in Patients with Severe Malarial Anemia and Appropriate Controls, and Determine if the High Expression Alleles are Associated with Severe Anemia, and 2) Define the Pathways Responsible for the Suppression of Erythropoiesis during Malaria Infection. We expect to establish that there is over-representation of high expression in patients with severe malarial anemia, and to define the intracellular mechanism by which MIF sustains ERK-1/2 activation and interferes with erythropoietin action. These results will be significant because they will provide a more precise understanding of the molecular pathways responsible for severe malarial anemia.