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

项目总结/摘要 萨摩亚是南太平洋的一个岛国（人口约20万）。几十年来，尽管水资源得到了改善， 质量和卫生，萨摩亚人面临着地方性伤寒，一个潜在的致命的人类宿主限制 伤寒：由伤寒沙门氏菌引起的血液、肝胆系统和肠道的细菌感染 （S.伤寒）。我们最近描述了萨摩亚地方性伤寒的流行病学，按个人、地点和 时间（Sikorski等人，临床传染病，2020年），但维持传播的机制 - 是直接传播还是间接的环境放大-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 抗药性和毒力因素，以及检测疫情。与高分辨率流行病学和 地理空间数据（即，萨摩亚伤寒监测倡议产生的数据） 解释起源、演化、聚集和传播模式。我们的长期目标是研究 基因组群体结构和进化。使用WGS和联合收割机在萨摩亚传播伤寒 比较基因组学与地理空间流行病学，以帮助解释其地方性。大规模基因组 研究描述了侵袭性广泛耐药沙门氏菌的出现和全球传播。伤寒菌株， 但没有人关注萨摩亚。基因组学S.伤寒在萨摩亚不知道也不是日期或地理 介绍的来源。我们对176 S. 1992-2018年萨摩亚伤寒分离株 显示（i）一个独特的萨摩亚基因型，出现在世界其他地方，（ii）地理空间聚类的 基因组相关的分离株，和（iii）存在的独特的基因只发现在萨摩亚分离株。我们 假设一种独特的S.伤寒几十年前进入萨摩亚， 循环菌株和无症状的慢性胆囊携带者的菌株作为一个有效的长期 传染源和传染源。我们提出了两个具体的目标：（1）研究S.伤寒 在萨摩亚引起临床疾病，和（2）定义无症状的S。伤寒携带者（迄今为止N=24） 结合WGS和地理空间分析。将对萨摩亚分离株进行测序和组装， 然后与S.伤寒（约3，400个分离株），使用单核苷酸多态性 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炸分数比管道 以识别任何新的和/或缺失的基因。经过疾病建模研究所的资助培训，我们将 联合收割机的数据在S.伤寒分离株与临床，流行病学和地理空间 数据来展示当地的传播模式。这些详细的分析从未完成， 萨摩亚群岛伤寒，其结果将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.