Genomics of Salmonella Typhi in Samoa: Population structure and genomic epidemiology

项目摘要/摘要 萨摩亚是南太平洋的一个岛国(人口约20万)。几十年来，尽管水得到了改善 在质量和卫生方面，萨摩亚人面临着地方性伤寒，这是一种可能致命的人类宿主限制 伤寒沙门氏菌引起的血液、肝胆树和肠道细菌感染 (S.Typhi)。我们最近描述了萨摩亚地方性伤寒的流行病学，按人、地点和 时间(Sikorski等人，Accept，临床传染病，2020)，但维持传播的机制 --无论是直接传播还是间接环境放大--仍然未知。细菌全基因组 测序(WGS)是一种现代分子工具，可以建立系统发育关系，检测抗生素 抗药性和毒力因子，以及检测疫情。与高分辨率的流行病学和 地理空间数据(即萨摩亚伤寒监测倡议生成的数据)WGS可帮助 解释起源、进化、集群和传播模式。我们的长期目标是研究 利用WGS和TO技术研究萨摩亚地区伤寒沙门氏菌的基因组结构和进化 用比较基因组学和地理空间流行病学来帮助解释其地方性。大规模基因组学 研究描述了攻击性广泛耐药伤寒沙门氏菌的出现和全球传播， 但没有一个人把重点放在萨摩亚。萨摩亚的伤寒沙门氏菌基因组学未知，也不知道日期和地理 引言来源。1992-2018年萨摩亚176株伤寒沙门氏菌的WGS初步分析 显示(I)世界上没有其他地方出现的独一无二的萨摩亚人基因，(Ii)地理空间集群 (3)存在仅在萨摩亚分离株中发现的独特基因。我们 假设一种独特的伤寒沙门氏菌株几十年前进入萨摩亚并扩展到优势种 循环菌株和无症状慢性胆囊炎携带者的菌株长期有效 蓄水池和感染源。我们提出了两个具体的目标：(1)研究伤寒沙门氏菌的基因组学 在萨摩亚引起临床疾病，以及(2)确定无症状伤寒沙门氏菌携带者的作用(迄今N=24) 使用组合的WGS和地理空间分析。来自萨摩亚的分离株将被测序和组装，并 然后用单核苷酸多态性与全球收集的伤寒沙门氏菌(~3400株)进行比较 和贝叶斯进化系统发育分析。我们将应用我们实验室的大规模爆破率管道 以识别任何新的和/或缺失的基因。在疾病建模研究所资助的培训之后，我们将 将伤寒沙门氏菌分离株之间的基因组相关性数据与临床、流行病学和地理空间相结合 显示局部传播模式的数据。这些详细的分析从未在 其结果将被纳入公共卫生决策和政策。

Project Summary / Abstract Samoa is an island nation in the South Pacific (population ~200,000). For decades and despite improved water quality and sanitation, Samoans have faced endemic typhoid fever, a potentially fatal human host-restricted bacterial infection of the blood, hepatobiliary tree, and intestine caused by Salmonella enterica serovar Typhi (S. Typhi). We recently described the epidemiology of endemic typhoid fever in Samoa by person, place, and time (Sikorski et al., accepted, Clinical Infectious Diseases, 2020), but the mechanisms sustaining transmission – either direct spread or indirect environmental amplification – remain unknown. Bacterial whole genome sequencing (WGS) is a modern molecular tool that can establish phylogenetic relationships, test for antibiotic resistance and virulence factors, as well as detect outbreaks. Paired with high resolution epidemiologic and geospatial data (i.e., data generated by the Samoa Typhoid Fever Surveillance Initiative) WGS can help to explain origins, evolution, clustering, and transmission patterns. Our long-term goals are to examine the genomic population structure and evolution of S. Typhi circulating in Samoa using WGS and to combine comparative genomics with geospatial epidemiology to help explain its endemicity. Large-scale genomic studies describe the emergence and global spread of aggressive extensively-drug resistant S. Typhi strains, but none have focused on Samoa. The genomics S. Typhi in Samoa not known nor is the date or geographical source of introduction. Our preliminary WGS analyses of 176 S. Typhi isolates from Samoa from 1992-2018 show (i) an exclusive Samoan genotype that appears nowhere else in the world, (ii) geospatial clustering of genomically related isolates, and (iii) the presence of unique genes found only in the Samoan isolates. We hypothesize that a unique strain of S. Typhi entered Samoa decades ago and expanded into the dominant circulating strain, and asymptomatic chronic gallbladder carriers of the strain serve as an effective long-term reservoir and source of infection. We propose two Specific Aims: (1) characterize the genomics of S. Typhi causing clinical disease in Samoa, and (2) define the role of asymptomatic S. Typhi carriers (N=24 to date) using combined WGS and geospatial analyses. Isolates from Samoa will be sequenced and assembled and then compared with the global collection of S. Typhi (~3,400 isolates) using single nucleotide polymorphism and Bayesian evolutionary phylogenetic analyses. We will apply our lab's large-scale blast score ratio pipeline to identify any new and/or deleted genes. After funded training from the Institute for Disease Modeling we will combine the data on genomic relatedness among S. Typhi isolates with clinical, epidemiologic, and geospatial data to demonstrate local patterns of transmission. These detailed analyses have never been completed on Samoan S. Typhi, and the results will be integrated into public health decisions and policies.