Genomic Epidemiology of Campylobacter to Improve Disease Control in Low and Middle Income Countries

摘要 弯曲杆菌是世界范围内细菌性肠炎的主要病因之一， 全球分离株，特别是低收入和中等收入国家的耐药性， 疾病预防控制中心将耐药弯曲杆菌列为2019年严重威胁名单的首位。在过去十年 欧洲在基因组流行病学方面的重大投资为降低发病率的成功干预提供了信息 人类感染和后遗症，如吉兰-巴雷综合征。尽管有明确的证据表明弯曲杆菌 是发展中国家肠炎的主要原因，但来源归属方面的先进方法还没有 被用来确定导致人类疾病的主要感染源，或确定 对氟喹诺酮类和阿奇霉素均耐药的人类感染源（MDR弯曲杆菌）， 尽管他们的记录高发病率。在中低水平进行的弯曲杆菌有限的基因组研究 收入国家的分离株基因组存在重要差异， 人畜共患病的来源，这表明在这些环境中的传播动态与在高 收入国家。目前缺乏对人畜共患病来源种群的准确定量来源归因 大多数感染发生在哪里是全球控制弯曲杆菌感染的关键知识差距。的 该项目的目标是为有针对性的疾病控制措施提供信息，以减少 弯曲杆菌病和人类MDR弯曲杆菌。我们的中央 一种假说认为，工业生产的肉制品是弯曲菌病和MDR的主要来源 弯曲杆菌在人群中的分布。为了检验我们的中心假设，我们将1）识别宿主 从秘鲁的人畜共患来源中分离弯曲杆菌的特征; 2）表征 导致人类疾病的弯曲杆菌菌株，评估家庭个人对个人的风险 传播和确定与持续无症状人类携带相关的微生物基因组特征 和3）估计弯曲杆菌病和人MDR感染的负担， 工业衍生的人畜共患病来源。拟议的项目将联合一个高度互补的小组， 在流行病学、弯曲杆菌基因组学、生物信息学和 微生物生态学为战略和有针对性的疾病控制干预措施提供信息， 人类MDR弯曲杆菌感染率最高的地区之一。该项目 在高负担低收入中等收入国家中将特征性人间病例与人畜共患病宿主联系起来的方法具有创新性 设置本地、区域和全球参考基因组，以创建强有力的证据来推动政策和实践 提高对弯曲杆菌病的控制和减少MDR的地理扩展 弯曲杆菌

ABSTRACT Campylobacter is among the principal causes of bacterial enteritis worldwide and the progressive development of antimicrobial resistance among global isolates, particularly in low and middle income countries, has led the CDC to list drug-resistant Campylobacter at the top of its list of serious threats in 2019. In the past decade in Europe major investments in genomic epidemiology have informed successful interventions to decrease rates of human infection and sequelae such as Guillan-Barre syndrome. Despite clear evidence that Campylobacter is a principal cause of enteritis in the developing world, advanced approaches in source attribution have not been employed to identify the principal sources of infection causing disease in humans, or to identify the sources of human infections resistant to both fluoroquinolones and azithromycin (MDR Campylobacter), despite their documented high incidence. The limited genomic study of Campylobacter done in low and middle income countries demonstrates important differences in the genomes of isolates from both humans and zoonotic sources, indicating that transmission dynamics differ in these settings compared to that seen in high income countries. The current deficit in accurate quantitative source attribution to zoonotic source populations where most infections occur is a critical knowledge gap in the global control of Campylobacter infections. The objective of this project is to inform targeted disease control measures to reduce the impact of campylobacteriosis and human MDR Campylobacter in low and middle income countries. Our central hypothesis is that industrially produced meat products are the principal source of campyobacteriosis and MDR Campylobacter in humans in this population. In order to test our central hypothesis we will 1) identify host segregating features of Campylobacter from zoonotic sources in Peru; 2) characterize genomes of Campylobacter strains that cause disease in humans, evaluate the risk of household peron-to-person transmission and identify microbial genomic features associated with persistent asymptomatic human carriage and 3) estimate the burden of campylobacteriosis and human MDR infections attributable to domestic and industrially derived zoonotic sources. The proposed project will unite a highly complementary group of accomplished researchers with expertise in epidemiology, Campylobacter genomics, bioinformatics and microbial ecology 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 its approach to link characterized human cases and zoonotic reservoirs in a high burden LMIC setting to local, regional, and global reference genomes to create robust evidence to drive policy and practice to improve the control of campylobacteriosis and the diminish the geographic expansion of MDR Campylobacter.