Defining serologic correlates of human hookworm infection

定义人类钩虫感染的血清学相关性

基本信息

批准号：
10667901
负责人：
MICHAEL CAPPELLO
金额：
$ 25.13万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-18 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667901
关键词：
Adult Africa South of the Sahara African Albendazole Allergens Anemia Animal Model Animals Antibodies Antibody Response Antigen Targeting Antigens Attention Automobile Driving Biological Assay Biology Blinded Blood Child Childhood Collaborations Communities Country Data Demographic Factors Developing Countries Development Diagnostic Procedure Disease Surveillance Dose Drug resistance Early Diagnosis Effectiveness Environment Enzyme-Linked Immunosorbent Assay Epidemiology Equipment Future Generations Genome Ghana Goals Growth HIV Hamsters Health Policy Helminths Hookworm Infections Hookworms Human Human Resources Immune response Immunity Immunoglobulin G Immunoprecipitation Impaired cognition Individual Infection Interruption Intestines Label Laboratories Laboratory Animal Models Malaria Malnutrition Measures Mediating Medical Research Medicine Methods Microscopy Modeling Monitor Morbidity - disease rate Necator americanus Nematoda Old World Hookworm Parasites Pathogenesis Peptide Mapping Persons Pharmaceutical Preparations Pharmacologic Substance Populations at Risk Positioning Attribute Predisposition Pregnant Women Prevalence Productivity Proteins Proteomics Public Health Public Health Practice Reagent Recombinant Proteins Recombinants Recommendation Research Research Personnel Resource-limited setting Role Sampling Serology Serum Soil Specificity Study Subject Testing Time Tissues Training Tuberculosis Universities Vaccines World Health Organization acquired immunity benzimidazole chronic infection design drug distribution epidemiology study experience experimental study feeding field study global health helminth infection high risk population human data human study immunoreactivity improved in vivo Model innovation insight low and middle-income countries molecular sequence database novel programs protein expression response risk prediction model screening secretory protein tool transmission process

项目摘要

PROJECT SUMMARY Hookworm infection is a leading cause of anemia, malnutrition and growth delay in poor countries, especially in sub-Saharan Africa, where millions of people are infected. Current strategies to control hookworm rely on Mass Drug Administration of anthelminthic drugs, although evidence calls into question the long-term effectiveness of this approach to sustainably control or eliminate hookworm in populations at risk. 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 in endemic communities. These studies have identified factors associated with hookworm infection status and response to deworming treatment. Preliminary data using human samples from Kintampo North, Ghana, suggests that host antibody (IgG) levels directed at hookworm adult worm excretory/secretory (ES) proteins are closely correlated with active infection. However, to date little is known about the targets of these antibody responses to hookworm antigens, which is a major gap in understanding of host-parasite interactions and pathogenesis. We hypothesize that host antibodies to specific hookworm proteins are predictive of infection status, and that a particular class of proteins, namely allergens, are the drivers of this response. Studies in Specific Aim 1 will validate the correlation between IgG antibody levels and infection status using 1,002 human serum samples and demographic data collected between 2007-2020 in Ghana field studies. Antibody levels will be measured by ELISA and analyzed for associations with hookworm infection status as determined by fecal microscopy. Data from human studies will be compared to results from controlled infection and treatment studies using the hamster model of Necator americanus. Studies in Aim 2 will focus on identifying the specific protein targets of host antibody responses using recombinant protein expression and Label Free Quantitative proteomics. Candidate hookworm allergen proteins will be expressed and purified, followed by screening for immunoreactivity using the human and hamster serum samples described in Aim 1. In addition, N. americanus adult worm ES proteins will be immunoprecipitated using highly reactive serum pools, followed by LC-MS/MS isolation and peptide mapping against hookworm/helminth genome sequence databases. These experiments will test the hypothesis that hookworm allergens are antigenic drivers of the host immune response that is associated with active infection. The overarching goals of the proposed research are to (1) correlate antibody responses with infection status and (2) characterize the role of hookworm allergens and novel antigenic proteins in host immune responses. These studies leverage a longstanding, productive collaboration between the University of Ghana and Yale that led to generation of novel preliminary data and adaptation of the first African hookworm strain in a laboratory model. These studies will enhance our understanding of hookworm pathogenesis and inform development of innovative tools to monitor deworming programs in endemic communities.

项目概要钩虫感染是贫穷国家贫血、营养不良和生长迟缓的主要原因，特别是在撒哈拉以南非洲地区，数百万人受到感染。目前控制钩虫的策略依赖于驱虫药的大规模药物管理局，尽管证据对长期效果提出质疑这种方法在可持续控制或消除高危人群中钩虫方面的有效性。自2007年以来，耶鲁大学和加纳大学野口纪念医学研究所合作研究了地方性社区中钩虫的流行病学特征。这些研究有确定了与钩虫感染状态和驱虫治疗反应相关的因素。初步的使用来自加纳 Kintampo North 的人类样本获得的数据表明，宿主抗体 (IgG) 水平针对钩虫成虫排泄/分泌（ES）蛋白与活动性感染密切相关。然而，迄今为止，人们对这些抗体对钩虫抗原反应的目标知之甚少，这是一个主要的问题。对宿主-寄生虫相互作用和发病机制的理解存在差距。我们假设宿主抗体特定的钩虫蛋白可以预测感染状态，并且一类特定的蛋白质，即过敏原是这种反应的驱动因素。具体目标 1 中的研究将验证 IgG 之间的相关性使用 1,002 份人类血清样本和收集的人口数据分析抗体水平和感染状态 2007年至2020年在加纳进行实地研究。将通过 ELISA 测量抗体水平并进行分析与粪便显微镜检查确定的钩虫感染状态的关联。来自人类研究的数据将与使用 Necator 仓鼠模型进行的受控感染和治疗研究的结果进行比较美洲努斯。目标 2 的研究将侧重于确定宿主抗体反应的特定蛋白质靶标使用重组蛋白表达和无标记定量蛋白质组学。候选钩虫过敏原蛋白质将被表达和纯化，然后使用人类和目标 1 中描述的仓鼠血清样品。此外，美洲 N. americanus 成虫 ES 蛋白将被使用高反应性血清池进行免疫沉淀，然后进行 LC-MS/MS 分离和肽图分析针对钩虫/蠕虫基因组序列数据库。这些实验将检验以下假设：钩虫过敏原是与活动性感染相关的宿主免疫反应的抗原驱动因素。拟议研究的总体目标是（1）将抗体反应与感染状态相关联 (2) 表征钩虫过敏原和新型抗原蛋白在宿主免疫反应中的作用。这些研究利用了加纳大学和耶鲁大学之间长期、富有成效的合作这导致了新的初步数据的产生以及第一个非洲钩虫菌株的适应实验室模型。这些研究将增强我们对钩虫发病机制的了解并为我们提供更多信息开发创新工具来监测流行社区的驱虫计划。