Genetic and Immunological Control for Development of Asymptomatic Malaria

无症状疟疾发展的遗传和免疫控制

• 批准号: 10260246
• 负责人: Tracey Jane Lamb
• 金额: $ 22.88万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10260246
• 关键词: 2 year old; Adult; Age; Alleles; Anemia; Animal Model; Antibody Response; Area; Blood Circulation; Blood Vessels; Cameroon; Candidate Disease Gene; Central Africa; Cessation of life; Characteristics; Child; Childhood; Clinical; Complex; Data; Development; Erythrocytes; Event; Exposure to; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Goals; Human; Immune; Immunologic Factors; Immunologics; Immunology; Individual; Infection; Inflammatory Response; Innate Immune Response; Knowledge; Laboratories; Lead; Malaria; Maps; Mediating; Mission; Modeling; Mus; Mus musculus domesticus; Parasitemia; Parasites; Pathogenesis; Peripheral; Phenotype; Plasmodium; Plasmodium berghei; Plasmodium yoelii; Population; Prevalence; Public Health; Quantitative Trait Loci; Research; Research Personnel; Resolution; Risk; Rodent Model; Salmonella infections; Symptoms; Syndrome; System; Testing; Time; United States National Institutes of Health; Vaccines; Variant; Work; adaptive immune response; adaptive immunity; cell type; comorbidity; disability; experience; gene discovery; genetic analysis; germ free condition; human disease; human model; malarial anemia; monocyte; mouse model; non-typhoidal Salmonella; pathogen; trait; transmission process

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.

摘要 疟疾是流行地区的一个重大问题，约有30亿人处于危险之中，200多人处于危险之中。 100万临床病例，造成40万至50万人死亡。然而，大多数人口 疟疾流行地区（>60%）没有症状（没有明显症状），即使在高传播地区也是如此。 虽然通过循环中循环的疟原虫感染的红细胞（iRBC）来识别，但术语 无症状疟疾是一种用词不当的个体经历轻度贫血和血管激活， 易患并发症，如非伤寒沙门氏菌感染，并作为水库， 感染假设是由几年来建立的适应性免疫控制，这是不太可能的。 该病例发生在2岁以下患有无症状疟疾的幼儿中。长期目标是 一个项目是确定遗传和免疫机制，使无症状的疟疾在年轻人 在儿童出现强大的适应性免疫之前。我们的首要假设是遗传变异 导致不同的先天免疫应答是控制无症状疟疾的原因。的 控制无症状疟疾的免疫学和遗传学基础尚不清楚， 完整的啮齿动物模型来剖析等位基因变异和个体免疫组分的贡献。 我们的工作假设是，协作杂交（CC）小鼠系，感染约氏疟原虫后， XNL，模型人类遗传变异，以允许鉴定与轻症发展相关的QTL 贫血，这是一种与人类无症状疟疾相关的特征。我们使用特定病原体的初步数据 野生捕获的遗传变异的小家鼠在贫血方面表现出广泛的变化， 疟原虫感染后的先天免疫反应表明，小鼠的遗传变异可以 可以用来确定与无症状疟疾有关的免疫机制。遵循这一 根据初步数据，所提出的工作将在一个特定目标下进行：表型38 CC小鼠 系，以鉴定控制贫血水平和先天免疫应答的QTL。 疟原虫感染。三个子目标将1）确定哪些CC小鼠品系发展为无症状的 2）开始绘制QTL图谱，并鉴定与疟疾发生相关的候选基因。 3）测试无症状疟疾与一种强有力的 先天免疫反应一旦完成，拟议的工作预计将确定关键的QTL， 小鼠疟疾贫血，并发现与无症状性贫血相关的候选基因和遗传网络。 疟疾这项研究是重要的，因为通过识别在特定条件下表现出有限贫血的细胞系， P.我们现在将首次提供一个基因完整的啮齿动物模型， 用来了解无症状疟疾是如何在基因和免疫上得到控制的。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。