Suppression of Erythropoiesis in Malaria Infection

描述（由申请人提供）：本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展有关，并表征MIF在疟疾环境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。感染并发症可导致死亡，其中包括严重和难治性贫血。最近在灵长类动物身上开发疟疾疫苗的尝试也受到疫苗接种和感染后严重贫血的阻碍。这些贫血的病理生理机制尚不清楚。我们发现MIF在许多疟疾感染个体中高水平表达，抑制红细胞祖细胞的发育，并拮抗促红细胞生成素信号。因此，MiF的作用反映了许多严重疟疾性贫血患者的临床分析。本应用程序的目的是确定高MIF表达的病理基础和MIF干扰红系祖细胞发育的机制。核心假设是，严重的疟疾贫血是遗传易感的结果，即MIF过度产生，加上MIF通过诱导ERK-1/2 MAP激酶级联的持续激活来抑制红细胞生成。我们在实验研究的基础上提出了这一假设，首先，MIF在疟疾感染期间在血液和骨髓中表达，其次，Mifgene的启动子存在多态性，影响其表达水平，第三，MIF抑制红细胞祖细胞的发育。本研究的具体目的是：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；2)确定疟疾感染期间抑制红细胞生成的途径。我们期望在严重疟疾性贫血患者中建立高表达的过度代表，并确定MIF维持ERK-1/2激活和干扰促红细胞生成素作用的细胞内机制。这些结果将具有重要意义，因为它们将提供对导致严重疟疾性贫血的分子途径的更精确理解。

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.