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