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引起细菌性肠炎的主要原因之一，并且正在逐步发展 在全球分离株中，特别是在低收入和中等收入国家，抗药性的增加导致了 CDC将耐药弯曲杆菌列为2019年严重威胁名单的首位。在过去的十年中， 欧洲在基因组流行病学方面的重大投资为降低发病率提供了成功的干预措施 人类感染和后遗症，如格林-巴利综合征。尽管有明确证据表明弯曲杆菌 是发展中国家肠炎的主要原因，在源头归属方面的先进方法尚未 被用来识别导致人类疾病的主要感染源，或识别 对氟喹诺酮类药物和阿奇霉素耐药的人类感染源(耐多药弯曲杆菌)， 尽管记录在案的发病率很高。中低位弯曲菌的有限基因组研究 收入国家显示出人类和人类分离株基因组的重要差异 人畜共患病来源，表明这些环境中的传播动态与在HIGH中看到的不同 收入国家。目前在准确量化来源归因于人畜共患病来源人群方面的不足 大多数感染发生的地方是在全球控制弯曲杆菌感染方面的关键知识缺口。这个 该项目的目标是提供有针对性的疾病控制措施，以减少 低收入和中等收入国家的弯曲杆菌病和人类耐多药弯曲杆菌。我们的中央 假设工业生产的肉制品是弯曲杆菌病和多药耐药的主要来源 在这个种群中的人类中存在弯曲杆菌。为了测试我们的中心假设，我们将1)确定宿主 从秘鲁人兽共患病来源中分离出弯曲杆菌的特征；2)描述 在人类中引起疾病的弯曲杆菌菌株，评估家庭中人与人之间传播的风险 传播和鉴定与持续性无症状人类携带者相关的微生物基因组特征 以及3)估计可归因于家庭和家庭的弯曲杆菌病和人类MDR感染的负担 工业来源的人畜共患病来源。拟议的项目将联合一组高度互补的 具有流行病学、弯曲杆菌基因组学、生物信息学和 微生物生态学为控制弯曲菌提供战略性和针对性的疾病控制干预措施 该地区是人类耐多药弯曲杆菌感染率最高的地区之一。该项目是 在高负担的LMIC中将典型的人间病例和人畜共患病例联系起来的方法具有创新性 设置为本地、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 加强弯曲杆菌病的控制，减少耐多药菌群的地域扩张 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.