Genomic features of host adaptation of Campylobacter in low-income settings

摘要 有强有力的流行病学证据表明，人类适应了人畜共患病病原体弯曲杆菌。然而， 这种适应的基因组特征还没有得到系统的评估。这样做的总体目标是 项目是确定弯曲杆菌的特定基因组特征，这些特征与适应 人类主持人，长期目标是将这一知识应用于全球参考数据库，以告知主持人 归因于和指导改进的疾病控制措施，以减轻全球弯曲菌的负担 人类的疾病。我们的中心假设是，在高度流行的环境中，长期暴露于 对人类宿主的适应性，而不是我们通常观察到的短暂感染流行病学 弯曲杆菌。此前人类适应的证据曾被认为是通过长时间携带 免疫抑制的患者和某些与人类疾病有关的弯曲杆菌谱系 慢性后遗症，如GBS，在人类宿主之外很少发现。我们已经确定了这些 在秘鲁亚马逊地区进行的两项纵向队列研究中的观察结果，这两项研究累计超过1400项 儿童年监测，20,000份粪便样本和850株弯曲杆菌分离株。具体地说，我们证明了a) 超过70%的儿童持续感染和携带弯曲杆菌，并获得0至24个月的完整随访， B)与全球临床收集的空肠弯曲菌相比，来自人类的高水平空肠弯曲菌菌株多样性 基因组，c)仅在人类宿主中描述的菌株的高比例(如ST-403、ST2802和ST- 2993)，与全球参考样本相比，以及d)显著缩小了人类基因组大小 空肠弯曲菌基因组与全球参考文献的比较。为了检验我们的假设，我们将 1)确定人类持续感染弯曲杆菌的基因组特征，以及2)确定 时空聚集性感染代表人与人之间的传播。拟议中的项目将联合起来 一个高度互补的团队，由具有流行病学、进化论专业知识的资深研究人员组成 生物学、弯曲杆菌基因组学和生物信息学，为战略性和针对性的疾病控制提供信息 在人类耐多药率最高的地区进行弯曲杆菌控制的干预措施 弯曲杆菌感染。[该项目的创新之处在于，它应用了微生物GWAS方法来进行资本化 关于从定义明确的纵向队列研究中获得的有效识别宿主的特殊菌株库 适应。][这项研究产生的人类宿主适应的高质量证据将是范例 转向控制弯曲杆菌的策略，可能会改变临床治疗 弯曲杆菌肠炎。]

ABSTRACT There is strong epidemiologic evidence of human adaption of the zoonotic pathogen Campylobacter. However, the genomic features of such adaptation have not been systematically evaluated. The overall objective of this project is to identify specific genomic features of Campylobacter that are associated with adaptation to the human host with the long-term goal of applying this knowledge to global reference databases to inform host attribution and guide improved disease control measures to reduce the global burden of Campylobacter disease in humans. Our central hypothesis is that in highly endemic settings, long-term exposure has allowed adaptation to the human host, as opposed to the transient infection epidemiology we usually observe with Campylobacter. Previous evidence of human adaption has been previously suggested by prolonged carriage in immunosuppressed patients and that certain Campylobacter lineages associated with human disease and chronic sequelae such as GBS, are rarely found outside the human host. We have identified these observations in two longitudinal cohort studies in the Peruvian Amazon that cumulatively comprise over 1400 child-years of surveillance, 20,000 stool samples and 850 Campylobacter isolates. Specifically, we evidence a) persistent Campylobacter infection and carriage in over 70% of children with complete 0 to 24-month follow-up, b) high-level of C. jejuni strain diversity derived from humans compared to the global collection of clinical genomes, c) high proportion of strains described exclusively in human hosts (such ST-403, ST2802 and ST- 2993), as compared to the global reference collection and d) considerable reduced genome size of human derived C. jejuni genomes compared to the global reference collection. In order to test our hypothesis, we will 1) Identify genomic features of persistent Campylobacter infections in humans, and 2) Determine if spatiotemporally clustered infections represent human to human transmission. The proposed project will unite a highly complementary group of accomplished researchers with expertise in epidemiology, evolutionary biology, Campylobacter genomics, and bioinformatics to inform strategic and targeted disease control interventions for Campylobacter control in an area with one of the highest documented rates of human MDR Campylobacter infection. [The project is innovative in the way it applies microbial GWAS methods to capitalize on an exceptional strain bank derived from well-defined longitudinal cohort studies to efficiently identify host adaptation.] [High quality evidence of human host adaptation generated by this study would be paradigm shifting to strategies used to control Campylobacter and would likely to alter the clinical management of Campylobacter enteritis.]