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

项目摘要/摘要 最近的研究发现，弯曲杆菌与慢性营养不良之间存在很强的关联， 在低资源环境中的儿童中，线性增长步履蹒跚就是明证。然而，个人的重要性 弯曲杆菌的种类和潜在的这种联系的机制还没有定义。同时， 水、环境卫生和个人卫生(WASH)综合干预措施未能改善线性增长或 即使是为了减少弯曲杆菌的流行。更好地了解流行性感冒的流行病学和负担 弯曲杆菌感染以及暴露于不同弯曲杆菌的蓄水池和途径 需要感染来指导下一代WASH研究和其他干预措施，以减少发育迟缓，以及 弯曲杆菌和不良线性生长之间的潜在联系的具体途径需要 已确认身份。我们的团队开创了定量分子诊断的先河，应用于广泛的 病原体对腹泻病因和肠道感染对生长的影响的研究。这些研究已经 揭示了细菌培养的局限性，这模糊了流行率和 弯曲杆菌物种多样性的重要性。我们已经开发了一种高通量、独立于文化的 使用有针对性的长读下一代测序的诊断方法，这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物种，包括猪肠道弯曲杆菌的高流行率， 在我们坦桑尼亚的出生队列中，这种病毒的流行率是朱尼杆菌的两倍多。在目标1中，我们将应用此诊断 描述三个低资源区儿童弯曲杆菌流行情况及影响的方法 设置，使用从多地点Mal-Ed出生队列收集的粪便样本中先前存档的DNA 在秘鲁的洛雷托、孟加拉国的达卡和坦桑尼亚的海顿学习。这将建立特定于物种的 腹泻的患病率、特定物种的归因发病率、危险因素以及与不良线性关系 成长。在目标2中，我们将描述海顿更大的出生队列中弯曲杆菌物种感染的特征， 坦桑尼亚确认目标1中确定的与增长的联系，并确定潜在的机制 这些联想。我们将专门测试一种假设，即免疫驱动的肠道动力受损 对细胞致死性膨胀毒素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机制相比的相对重要性 小路。在目标3中，我们将在坦桑尼亚的海顿建立一个传播队列，以了解主要 在这个非洲农村环境中，弯曲杆菌感染的蓄水池和途径。总而言之，这项工作将 建立

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