Genetic and Immunological Control for Development of Asymptomatic Malaria

摘要 疟疾在流行地区是一个严重的问题，那里有大约30亿人处于危险之中，超过200人 10万例临床病例，造成40万至50万人死亡。然而，大多数人口在 疟疾流行区(60%)没有症状(没有明显症状)，即使在高传播区也是如此。 虽然通过循环中的受疟原虫感染的红细胞(IRBC)来识别，但术语 无症状疟疾是一个用词不当的词，指个体经历轻度贫血和血管激活， 易受非伤寒沙门氏菌感染等共病的影响，并可作为 感染。假设这是由经过几年积累的获得性免疫控制的，这不太可能是 该病例发生在2岁以下患有无症状疟疾的幼儿身上。这样做的长期目标是 该项目是确定在年轻人中产生无症状疟疾的遗传和免疫学机制。 儿童在发病前有强健的适应性免疫。我们最重要的假设是基因变异 导致不同的先天免疫反应是控制无症状疟疾的原因。这个 目前尚不清楚控制无症状疟疾的免疫学和遗传学基础--没有遗传学上的 完整的啮齿动物模型，解剖等位基因变异和个体免疫成分的贡献。 我们的工作假设是，当感染约氏疟原虫时，协同杂交(CC)小鼠品系 XNL，模拟人类遗传变异，以识别与轻度痴呆发生相关的QTL 贫血，一种与人类无症状疟疾有关的特征。我们使用特定病原体的初步数据 野生(SPF)捕获的遗传变异家鼠表现出广泛的贫血和 疟原虫感染后的先天免疫反应表明，小鼠的遗传变异可以 被利用来确定与无症状疟疾相关的免疫机制。以此为指导 初步数据，建议的工作将在一个特定的目标下进行：表型38 CC小鼠 识别控制贫血水平和先天免疫反应的QTL的品系 疟原虫感染。三个子目标将1)决定哪些CC小鼠品系发展为无症状 疟疾2)开始定位QTL并确定与发展有关的候选基因 小鼠的无症状疟疾3)检验无症状疟疾与强健的 先天免疫反应。一旦完成，拟议的工作预计将确定潜在的关键QTL 在小鼠中发现疟疾贫血并发现与无症状相关的候选基因和遗传网络 疟疾。这项拟议的研究具有重要意义，因为通过识别出表现为局限性贫血的线条 我们现在将首次提供一种基因完整的啮齿动物模型，该模型可以 用于了解无症状疟疾是如何通过遗传和免疫控制的。这将包括 无症状疟疾如何影响共同感染的病原体和儿童疫苗的效力。

Abstract Malaria is a significant problem in endemic areas with approximately 3 billion people at risk and over 200 million clinical cases resulting in between 0.4 and 0.5 million deaths. However, the majority of the population in malaria endemic areas (>60%) is asymptomatic (without overt symptoms), even in high transmission areas. Although identified by circulating Plasmodium-infected red blood cells (iRBCs) in the circulation, the term asymptomatic malaria is a misnomer with individuals experiencing mild anemia and vascular activation, susceptible to co-morbidities such as non-typhoidal Salmonella infections, and acting as a reservoir for infection. Assumed to be controlled by adaptive immunity that builds over several years, this is unlikely to be the case in young children under the age of 2 who have asymptomatic malaria. The long-term goal of this project is to define the genetic and immunological mechanisms that confer asymptomatic malaria in young children before the onset of robust adaptive immunity. Our overarching hypothesis is that genetic variation leading to differential innate immune responses is responsible for controlling asymptomatic malaria. The immunological and genetic underpinnings governing asymptomatic malaria is unknown - there is no genetically intact rodent model to dissect the contributions of allelic variation and individual immunological components. Our working hypothesis is that the collaborative cross (CC) mouse lines, upon infection with Plasmodium yoelii XNL, model human genetic variation to allow identification of QTL associated with the development of mild anemia, a trait associated with asymptomatic malaria in humans. Our preliminary data using specific pathogen free (SPF) wild-caught genetically variable Mus musculus domesticus show a wide variation in anemia and innate immune responsiveness after Plasmodium infection demonstrating that genetic variation in mice could be harnessed to identify the immunological mechanisms associated with asymptomatic malaria. Guided by this preliminary data, the work proposed will be undertaken under a single specific aim: Phenotype 38 CC mouse lines to identify QTLs that govern the level of anemia and innate immune responsiveness to Plasmodium infection. Three sub-aims will 1) determine which CC mouse lines develop asymptomatic malaria 2) begin to map QTLs and identify gene candidates that are associated with development of asymptomatic malaria in mice 3) test the hypothesis that asymptomatic malaria is associated with a robust innate immune response. Once completed, the proposed work is expected to identify key QTLs underlying malarial anemia in mice and discover gene candidates and genetic networks associated with asymptomatic malaria. The proposed research is significant because by identifying the lines that display limited anemia upon P. yoelii XNL infection we will now provide, for the first time, a genetically intact rodent model which can be used to understand how asymptomatic malaria is genetically and immunologically controlled. This will include as how asymptomatic malaria influences co-infecting pathogens and efficacy of childhood vaccines.