Translational studies of hookworm infection in Ghana

加纳钩虫感染的转化研究

• 批准号: 10446294
• 负责人: MICHAEL CAPPELLO
• 金额: $ 79.65万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-22 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446294
• 关键词: Africa; Africa South of the Sahara; African; Aftercare; Age; Albendazole; Ancylostoma (genus); Anemia; Animal Model; Antibodies; Antibody Response; Antigens; Behavioral; Biology; Blood; Chronic; Clinical; Collaborations; Communicable Diseases; Communities; Complex; Country; Coupled; DNA; Data; Development; Disease; Drug Exposure; Drug Monitoring; Drug resistance; Effectiveness; Enrollment; Epidemiology; Evolution; Exposure to; Foundations; Future; Genes; Genetic; Genetic Models; Genetic Variation; Genomics; Ghana; Goals; Growth; HIV; Hamsters; Helminths; Hookworm Infections; Hookworms; Human; Immune response; Impaired cognition; Impairment; In Vitro; Infection; Infrastructure; Institutes; Intestines; Kinetics; Laboratories; Legal patent; Malaria; Malnutrition; Maternal and Child Health; Mediating; Medical Research; Methods; Mitochondria; Modeling; Monitor; Morbidity - disease rate; Mucous Membrane; Mutation; Necator americanus; Nematoda; Nutritional; Organizational Objectives; PTGS1 gene; Parasites; Pathogenesis; Pattern; Persons; Pharmaceutical Preparations; Pilot Projects; Play; Population; Population Genetics; Predisposition; Prevalence; Primary Infection; Proteins; Proteomics; Public Health; Reagent; Reporting; Reproducibility; Research; Research Personnel; Resistance; Resources; Risk; Risk Factors; Role; Soil; Study Subject; Techniques; Technology; Tuberculosis; Universities; Vaccination; World Health Organization; base; benzimidazole; beta Tubulin; disease transmission; egg; experience; experimental study; feeding; field study; genetic architecture; genomic tools; human data; human disease; human population genetics; immunopathology; in vivo; innovation; insight; low and middle-income countries; neglected tropical diseases; next generation sequencing; novel; novel strategies; nutrition; pressure; resistance frequency; response; secretory protein; tool; translational study; vaccine development; vaccine efficacy; vaccine response

PROJECT SUMMARY Hookworm infection is a leading cause of malnutrition and growth delay in poor countries, especially in sub- Saharan Africa where millions of people are infected with Necator americanus. Data from human studies suggest chronic hookworm infection also impairs routine vaccine efficacy and exacerbates other globally important, co-endemic infectious diseases. Current strategies to control hookworm rely primarily on Mass Drug Administration of standard anthelminthic drugs, although recent evidence calls into question the long-term effectiveness of this approach to control and eliminate hookworm in endemic populations. Since 2007, Yale University and the Noguchi Memorial Institute for Medical Research at the University of Ghana have collaborated to characterize the epidemiology of hookworm infection in endemic communities. The longitudinal field study proposed in Aim 1 will further probe the epidemiology of hookworm by defining risk factors for infection, response to deworming, and reinfection following treatment in the Bono East Region, Ghana. Experiments outlined in Aim 2 will be focused on characterizing changes in the frequency of resistance associated mutations in the N. americanus β-tubulin gene using Next Generation Sequencing methods, as well as the impact of drug pressure on genetic diversity and the population genetics of human hookworms in Beposo. Critical to the detailed study of hookworm pathogenesis is the availability of a facile animal model that is both reproducible and accurately reflects the major clinical features of human disease. Little is known about N. americanus strains originating from populations in Africa, resulting in a significant gap in our understanding of hookworm biology, genomics and evolution. Building on experience in maintaining the laboratory model of Ancylostoma ceylanicum hookworms, field isolates of N. americanus cultured from study subjects in Ghana in 2019 have been used to establish patent infections in hamsters. In the experimental studies outlined in Aim 3, clinical parameters and the kinetics of primary infection with the Ghana strain of N. americanus will be fully characterized in the hamster model. Cellular, humoral and mucosal antibody responses to primary infection, reinfection and vaccination with hookworm proteins will be defined. In addition, novel proteomic methods will be applied to define human antibody profiles that correlate with infection status, intensity and risk of reinfection. The overarching goals of the research outlined in this proposal are (1) to identify factors associated with hookworm infection among people living in Beposo, Ghana, (2) to characterize the impact of deworming pressure on drug resistance markers and genetic diversity of hookworms in Ghana and (3) to characterize the first laboratory adapted African strain of N. americanus and optimize its utility for the study of human hookworm epidemiology, pathogenesis and vaccine development. Results from these innovative studies will enhance our understanding of hookworm pathogenesis in Africa and inform future development of public health tools to reduce the global burden of this neglected tropical disease.

项目总结 钩虫感染是贫穷国家营养不良和生长迟缓的主要原因，特别是在亚 撒哈拉非洲，那里有数百万人感染美洲钩端螺旋体。来自人体研究的数据 表明慢性钩虫感染也削弱了常规疫苗的效力，并加剧了全球其他 重要的、共同流行的传染病。当前控制钩虫的策略主要依赖于大规模药物 使用标准驱虫药，尽管最近的证据令人怀疑其长期疗效 这一方法在控制和消除流行人群中钩虫的有效性。自2007年以来，耶鲁大学 大学和加纳大学野口纪念医学研究所 合作确定流行社区钩虫感染的流行病学特征。纵向的 目标1建议的实地研究将通过确定钩虫的危险因素，进一步探讨钩虫的流行病学。 加纳波诺东部地区的感染、驱虫反应和治疗后的再感染。 目标2中概述的实验将集中于表征抗性频率的变化。 用下一代测序方法研究美洲不动杆菌β-微管蛋白基因的相关突变 由于药物压力对人类钩虫遗传多样性和种群遗传学的影响 贝波索。对钩虫致病机理的详细研究的关键是有一种简便的动物模型的可用性 既可重复性，又能准确反映人类疾病的主要临床特征。人们对此知之甚少 起源于非洲人群的美洲奈瑟氏菌菌株，导致我们在理解上有很大差距 钩虫生物学、基因组学和进化论。以维护实验室模型的经验为基础 年从加纳研究对象培养的美洲钩虫钩虫 2019年已经被用来确定仓鼠的专利感染。在目标3概述的实验研究中， 临床参数和初次感染加纳株美洲奈瑟氏菌的动力学将完全 以仓鼠模型为特征。对初次感染的细胞、体液和粘膜抗体反应， 将定义钩虫蛋白的再感染和疫苗接种。此外，新的蛋白质组学方法将是 应用于定义与感染状态、强度和再感染风险相关的人类抗体图谱。 本提案中概述的研究的首要目标是(1)确定与以下因素相关的因素 生活在加纳贝波索的人群中的钩虫感染，(2)表征驱虫的影响 加纳钩虫耐药标记和遗传多样性的压力和(3)表征 首个实验室适应美洲钩虫非洲株并优化其在人钩虫研究中的应用 流行病学、发病机制和疫苗开发。这些创新研究的结果将增强我们的 了解非洲钩虫的发病机制，并为公共卫生工具的未来发展提供信息 减轻这一被忽视的热带病的全球负担。