Epidemiology and impact of diverse Campylobacter species in low-resource settings

资源匮乏环境中多种弯曲杆菌的流行病学和影响

• 批准号: 10030449
• 负责人: James Alexander Platts-Mills
• 金额: $ 39.29万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10030449
• 关键词: 16S ribosomal RNA sequencing; Address; Affect; African; Archives; Award; Bangladesh; Birth; Campylobacter; Campylobacter coli; Campylobacter hyointestinalis; Campylobacter infection; Child; Chronic; Cohort Studies; Communicable Diseases; DNA; Data; Development; Diagnostic; Diarrhea; Enteral; Environment; Epidemiology; Etiology; Evaluation; Exposure to; Failure; Feces; Funding; Genes; Goals; Growth; High Prevalence; Hormonal; Hygiene; Immune response; Impairment; Incidence; Individual; Infection; Infrastructure; International; Intervention; Intervention Studies; Knowledge; Life; Malnutrition; Metabolic; Modeling; Molecular; Molecular Diagnostic Techniques; Niacinamide; Outcome; Output; Pathway interactions; Peru; Prevalence; Protozoa; Research; Research Design; Research Personnel; Resources; Risk Factors; Route; Rural; Sampling; Sanitation; Schedule; Site; Small Intestines; Tanzania; Testing; Water; Work; antimicrobial; base; cell motility; cohort; cytolethal distending toxin; enteric infection; exposure pathway; improved; inflammatory marker; innovation; mathematical model; microbiota; molecular diagnostics; next generation; next generation sequencing; pathogen; programs; stool sample; transmission process

PROJECT SUMMARY/ABSTRACT Recent research has identified a strong association between Campylobacter and chronic malnutrition, evidenced by linear growth faltering, in children in low-resource settings. However, the importance of individual Campylobacter species and the mechanism underlying this association have not been defined. Meanwhile, comprehensive water, sanitation, and hygiene (WASH) interventions have failed to improve linear growth or even to reduce Campylobacter prevalence. A better understanding of the epidemiology and burden of Campylobacter infections as well as the reservoirs and pathways for exposure to diverse Campylobacter infections is needed to guide next-generation WASH studies and other interventions to reduce stunting, and the specific pathways underlying the association between Campylobacter and poor linear growth need to be identified. Our group has pioneered the application of quantitative molecular diagnostics for a broad range of pathogens to studies of diarrhea etiology and the impact of enteric infections on growth. These studies have revealed the limitations of bacterial culture, which has obscured characterization of the prevalence and importance of diverse Campylobacter species. We have developed a high-throughput, culture-independent diagnostic approach using targeted long-read next generation sequencing, which reveals a broad diversity of Campylobacter species in children in these settings, including a strikingly high prevalence of C. hyointestinalis, more than twice as prevalent as C. jeuni in our birth cohort in Tanzania. In Aim 1, we will apply this diagnostic approach to describe the epidemiology and impact of Campylobacter species in children in three low-resource settings, using previously archived DNA from stool samples collected from the multisite MAL-ED birth cohort study in Loreto, Peru, Dhaka, Bangladesh, and Haydom, Tanzania. This will establish the species-specific prevalence, species-specific attributable incidence of diarrhea, risk factors, and association with poor linear growth. In Aim 2, we will characterize Campylobacter species infections in a larger birth cohort in Haydom, Tanzania to validate the associations with growth identified in Aim 1 and to define mechanisms underlying these associations. We will specifically test the hypothesis that impaired gut motility driven by an immune response to cytolethal distending toxin B and associated small intestinal bacterial overgrowth is associated with poor linear growth. We will define the relative importance of this mechanism compared to other possible pathways. In Aim 3, we will establish a transmission cohort in Haydom, Tanzania to understand the major reservoirs of and pathways for Campylobacter infections in this rural African setting. In total, this work will establish the

项目概要/摘要 最近的研究发现弯曲杆菌与慢性营养不良之间存在密切关联， 资源匮乏地区儿童的线性生长缓慢就是证据。然而，个人的重要性 弯曲杆菌种类和这种关联的机制尚未确定。同时， 全面的水、环境卫生和个人卫生 (WASH) 干预措施未能改善线性增长或 甚至可以减少弯曲杆菌的流行。更好地了解流行病学和负担 弯曲杆菌感染以及接触不同弯曲杆​​菌的储存库和途径 需要通过感染来指导下一代 WASH 研究和其他干预措施以减少发育迟缓，并且 弯曲杆菌与线性生长不良之间关联的具体途径需要 确定。我们的团队率先将定量分子诊断应用于广泛的领域 病原体以研究腹泻病因和肠道感染对生长的影响。这些研究有 揭示了细菌培养的局限性，这模糊了患病率和 不同弯曲杆​​菌物种的重要性。我们开发了一种高通量、独立于文化的 使用靶向长读长下一代测序的诊断方法，揭示了广泛的多样性 在这些环境中的儿童中存在弯曲杆菌，其中猪肠道弯曲杆菌的患病率惊人地高， 在我们坦桑尼亚的出生队列中，C. jeuni 的流行率是 C. jeuni 的两倍多。在目标 1 中，我们将应用此诊断 描述三个资源匮乏地区的儿童中弯曲杆菌的流行病学和影响的方法 设置，使用先前存档的从多站点 MAL-ED 出生队列收集的粪便样本中的 DNA 在秘鲁洛雷托、孟加拉国达卡和坦桑尼亚海多姆学习。这将建立物种特异性 患病率、腹泻的物种特异性归因发病率、危险因素以及与不良线性关系的相关性 生长。在目标 2 中，我们将描述 Haydom 较大出生队列中弯曲杆菌属感染的特征， 坦桑尼亚验证目标 1 中确定的与增长的关联并定义潜在机制 这些协会。我们将专门测试免疫驱动的肠道蠕动受损的假设 对细胞致死膨胀毒素 B 的反应与相关的小肠细菌过度生长有关 线性增长较差。我们将定义该机制与其他可能的机制相比的相对重要性 途径。在目标 3 中，我们将在坦桑尼亚海多姆建立一个传播队列，以了解主要情况 非洲农村环境中弯曲杆菌感染的储存库和途径。总的来说，这项工作将 建立