The Role of Casual Contact and Migration in XDR TB Transmission in South Africa: a Geospatial, Genomic and Social Network Study

结核病（TB）是全球主要的传染病杀手，主要是由结核病的传播驱动的。 高发病率设置。然而，迄今为止的研究未能确定大多数 传输正在发生。传统上，结核病的传播归因于长期的密切接触，但 许多研究表明，只有9-30%的基因型连锁病例可归因于密切相关， contact.一个令人信服的替代假设是，其余70%的传播是由于偶然的 在社区里有联系但这从未被证实过更好地了解在哪里传播 将有助于设计更有效的干预措施来遏制结核病发病率。 在南非夸祖鲁-纳塔尔省开展的艾滋病毒相关广泛耐药结核病传播（TRAX）研究中， 广泛耐药结核病（XDR）主要是由传播而不是获得性驱动的 抵抗，推翻了普遍的信念。然而，与药物敏感性结核病相似， 耐药结核病病例可能通过密切接触联系在一起。耐药性结核病提供了一个独特的机会 研究由于偶然接触引起的传播，因为有限的病例数允许进行全面的基因分型， 确定在接触调查中可能相互指名道姓的个人之间的传播联系。 在拟议的研究中，我们将测试一个新的假设，即偶然的接触和迁移正在助长结核病 在高发病率环境中的传播。整个亚洲和非洲的城市化和移徙率不断上升 为结核病的传播创造了有利条件。然而，到目前为止，还没有研究全面研究 移民如何促进结核病从城市向农村的传播。在目标1中，我们将确定 通过偶然接触发展的广泛耐药结核病的比例，并确定发生传播的地点 使用基因组、社交网络和地理空间分析。在目标2中，我们将描述迁移模式 在德班被诊断为广泛耐药结核病的人中，以确定移民如何为广泛耐药结核病创造机会 结核病传播。在目标3中，我们将量化整个夸祖鲁-纳塔尔的XDR结核病例的比例 使用全基因组测序，发现与德班病例有基因组关联的省份。 背景中提出的目标（广泛耐药结核传播中的偶然接触和迁移） 研究建立在我们建立的研究基础设施和成功的跟踪记录相结合的国家的， 了解结核病传播的最新方法。这项研究的新知识将是必不可少的， 为循证干预措施提供信息，以阻止结核病传播，减少药物敏感和耐药 结核病发病率。这将包括与基因组相关的结核病病例的近实时数据，以及 这些地点将是减少空气传播的目标干预措施的最高产量。在一起， 从这项研究中产生的知识和综合方法将催化 全球结核病发病率需要实现全球终结结核病2035目标。

Tuberculosis (TB) is the leading infectious disease killer globally and is largely driven by transmission in high incidence settings. Studies to date, however, have not been able to identify where the majority of transmission is occurring. TB transmission has traditionally been attributed to prolonged, close contact, but numerous studies have shown that only 9–30% of genotypically linked cases can be attributed to close contact. A compelling alternative hypothesis is that the remaining 70% of transmission occurs due to casual contact in the community, but this has never been verified. A better understanding of where transmission occurs will enable the design of more effective interventions to curb TB incidence. In the Transmission of HIV-Associated XDR TB (TRAX) study in KwaZulu-Natal province, South Africa, we demonstrated that extensively drug-resistant (XDR) TB is primarily driven by transmission, rather than acquired resistance, overturning the prevailing belief. However, similar to drug-susceptible TB, less than one-third of drug-resistant TB cases could be linked through close contact. Drug-resistant TB provides a unique opportunity to study transmission due to casual contact, as the limited caseload allows for comprehensive genotyping to identify transmission links between individuals who may name each other in a contact investigation. In the proposed study, we will test a novel hypothesis that casual contact and migration are fueling TB transmission in high incidence settings. Rising rates of urbanization and migration throughout Asia and Africa have created favorable conditions for TB transmission. Yet, to date, no studies have comprehensively studied how migration may facilitate the spread of TB from urban to rural settings. In Aim 1, we will determine the proportion of XDR TB that develops through casual contact and identify locations where transmission occurs using genomic, social network, and geospatial analyses. In Aim 2, we will characterize migration patterns among persons diagnosed with XDR TB in Durban to determine how migration creates opportunities for XDR TB dissemination. In Aim 3, we will quantify the proportion of XDR TB cases from throughout KwaZulu-Natal province that are genomically linked to cases in Durban using whole genome sequencing. The aims proposed in the CONTEXT (Casual Contact and Migration in the Transmission of XDR TB) study build upon our established research infrastructure and successful track record of combining state-of-the- art methodologies to gain insight into TB transmission. New knowledge from this study will be essential for informing evidence-based interventions to halt TB transmission and reduce drug-susceptible and drug-resistant TB incidence. This will include near real-time data on genomically linked TB cases, as well as the identification of locations that will be highest yield for targeting interventions to decrease airborne transmission. Together, the knowledge and integrated methodology created from this study will catalyze the significant declines in global TB incidence needed to achieve the global EndTB 2035 goals.