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: 10415195
• 负责人: Tracey Jane Lamb
• 金额: $ 19.06万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415195
• 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; Persons; 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.

抽象的 疟疾在流行地区是一个重大问题，大约有30亿人处于危险之中，超过200人 数百万个临床病例导致0.4至50万人死亡。但是，大多数人口 疟疾流行区域（> 60％）是无症状的（没有明显的症状），即使在高传输区域也是如此。 尽管通过循环中的循环质量感染的红细胞（IRBC）鉴定 无症状疟疾是一种错误的称呼，患有轻度贫血和血管激活的个体， 容易受到合并症，例如非肾脏沙门氏菌感染，并充当储层 感染。假定由几年来建立的自适应免疫控制，这不太可能是 在2岁以下的幼儿中，患有无症状疟疾的案件。这个长期目标 项目是定义赋予年轻疟疾无症状疟疾的遗传和免疫学机制 健壮的自适应免疫发作之前的孩子。我们的总体假设是遗传变异 导致先天免疫反应的差异负责控制无症状的疟疾。这 免疫和遗传基础无症状疟疾尚不清楚 - 没有遗传 完整的啮齿动物模型，以剖析等位基因变异和个体免疫学成分的贡献。 我们的工作假设是，在感染疟原虫时，协作交叉（CC）小鼠线 XNL，模型的人遗传变异，以识别与轻度发展相关的QTL 贫血，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 自由（SPF）野生遗传上的遗传变化us usculus fordiesus表现出贫血和 疟原虫感染后的先天免疫反应能力，表明小鼠的遗传变异可能 要利用与无症状疟疾相关的免疫机制。以此为指导 初步数据，提出的工作将以一个特定的目的进行：表型38 cc鼠标 识别QTL的行，该QTL控制贫血和先天免疫反应的水平 疟原虫感染。三个子iams将1）确定哪些CC鼠标线出现无症状 疟疾2）开始绘制QTL并确定与发展有关的基因候选者 小鼠中无症状的疟疾3）检验了无症状疟疾与健壮有关的假设 先天免疫反应。完成后，预计拟议的工作将确定基础的关键QTL 小鼠中的疟疾贫血，发现候选基因和遗传网络与无症状有关 疟疾。拟议的研究很重要，因为通过识别显示有限的贫血的线 P. yoelii XNL感染现在我们将首次提供一个遗传完整的啮齿动物模型 用于了解无症状的疟疾在遗传和免疫学上是如何控制的。这将包括 作为无症状疟疾如何影响儿童疫苗的共同感染病原体和功效。