Genetic and Immunological Control for Development of Asymptomatic Malaria

无症状疟疾发展的遗传和免疫控制

基本信息

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
项目类别：
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

项目摘要

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.

抽象的疟疾是流行地区的一个严重问题，约有 30 亿人面临风险，200 多人万临床病例导致 0.4 至 50 万人死亡。然而，大多数人口在疟疾流行地区（>60%）是无症状的（没有明显症状），即使在高传播地区也是如此。尽管通过循环中感染疟原虫的红细胞 (iRBC) 进行识别，但该术语无症状疟疾是一个误称，指的是患有轻度贫血和血管活化的个体，容易受到非伤寒沙门氏菌感染等合并症的影响，并成为细菌的储存库感染。假设是由数年建立的适应性免疫控制的，这不太可能是该病例发生在患有无症状疟疾的 2 岁以下幼儿中。本次活动的长远目标该项目的目的是确定导致年轻人罹患无症状疟疾的遗传和免疫机制儿童在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反应负责控制无症状疟疾。这控制无症状疟疾的免疫学和遗传基础尚不清楚——没有遗传因素完整的啮齿动物模型，用于剖析等位基因变异和个体免疫成分的贡献。我们的工作假设是，协作交叉（CC）小鼠系在感染约氏疟原虫后 XNL，人类遗传变异模型，可鉴定与轻度疾病发展相关的 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）野生捕获的遗传变异家鼠在贫血和贫血方面表现出很大的差异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用于确定与无症状疟疾相关的免疫机制。以此为指导根据初步数据，拟议的工作将在一个具体目标下进行：表型 38 CC 小鼠品系来鉴定控制贫血水平和先天免疫反应的 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疟疾 2) 开始绘制 QTL 图谱并识别与疟疾发展相关的候选基因小鼠无症状疟疾 3) 检验无症状疟疾与强效疟疾相关的假设先天免疫反应。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相关的候选基因和遗传网络疟疾。拟议的研究意义重大，因为通过识别显示有限贫血的细胞系 P. yoelii XNL 感染，我们现在将首次提供遗传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基因和免疫学控制的。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功效。