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

项目总结/摘要 最近的研究已经确定弯曲杆菌和慢性营养不良之间有很强的联系， 在低资源环境下的儿童中，线性增长步履蹒跚。然而，个人的重要性 弯曲杆菌的物种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， 甚至减少弯曲杆菌的流行。更好地了解流行病学和 弯曲杆菌感染以及暴露于不同弯曲杆菌的储存库和途径 需要对感染进行评估，以指导下一代WASH研究和其他干预措施，减少发育迟缓， 弯曲杆菌和线性生长不良之间的相关性的具体途径需要 鉴定我们的团队率先将定量分子诊断应用于广泛的 病原体的研究腹泻病因学和肠道感染对生长的影响。这些研究 揭示了细菌培养的局限性，这掩盖了患病率的特征， 不同种类的弯曲杆菌的重要性。我们已经开发出一种高通量的，不依赖于培养的 使用靶向长读段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，儿童中的弯曲杆菌物种，包括C。猪链球菌， 比C.在坦桑尼亚出生的年轻人中。在目标1中，我们将应用此诊断 一种描述三个低资源国家儿童中弯曲杆菌属的流行病学和影响的方法 设置，使用先前存档的DNA从粪便样本收集的多地点MAL-ED出生队列 在秘鲁的洛雷托、孟加拉国的达卡和坦桑尼亚的海顿学习。这将建立物种特异性 腹泻的患病率、种属特异性归因发病率、危险因素以及与不良线性相关性 增长在目标2中，我们将在海顿的一个较大的出生队列中描述弯曲杆菌属感染的特征， 坦桑尼亚将验证目标1中确定的与增长的联系，并确定其机制 这些协会。我们将专门检验一个假设，即由免疫系统驱动的肠道运动受损， 对致死性膨胀毒素B的反应和相关的小肠细菌过度生长相关 线性增长差。我们将定义这种机制与其他可能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，以了解主要的 弯曲杆菌感染的储存库和途径。总的来说，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