Improved understanding of TB transmission by accounting for within-host heterogeneity of M. tuberculosis: A population-based molecular epidemiology study in a high HIV prevalent setting

通过考虑结核分枝杆菌的宿主内异质性，提高对结核病传播的理解：在艾滋病毒高流行环境中进行的基于人群的分子流行病学研究

• 批准号: 10327709
• 负责人: Sanghyuk Sam Shin
• 金额: $ 62.42万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-07 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10327709
• 关键词: Accounting; Address; Affect; Area; Bioinformatics; Botswana; Categories; Cessation of life; Church; Cluster Analysis; Cohort Studies; Collaborations; Communities; DNA; Data; Detection; Development; Disease; Effectiveness; Enrollment; Epidemic; Epidemiology; Future; Genetic; Genotype; Goals; HIV; HIV Infections; HIV/TB; Heterogeneity; High Prevalence; Household; Incidence; Individual; Infection; Integration Host Factors; Interruption; Intervention; Knowledge; Lead; Methods; Modeling; Molecular; Molecular Analysis; Molecular Epidemiology; Molecular Profiling; Morbidity - disease rate; Mutation; Mycobacterium tuberculosis; Mycobacterium tuberculosis complex; Natural History; Pathogen detection; Persons; Phylogenetic Analysis; Population; Predictive Factor; Predisposition; Prevalence; Public Health; Research; Research Infrastructure; Resistance; Sampling; Sampling Biases; Source; Sputum; Tuberculosis; base; case finding; co-infection; combat; epidemiologic data; epidemiology study; genome sequencing; genomic locus; improved; indexing; mortality; multimodality; novel; pathogen; population based; prospective; resistance mutation; response; social; statistical learning; transmission process; whole genome

ABSTRACT In high tuberculosis (TB) incidence settings, individuals with TB are often infected with multiple strains of M. tuberculosis complex (Mtbc). Despite this known fact, current TB transmission studies largely ignore within-host Mtbc heterogeneity. We believe that accounting for within-host Mtbc heterogeneity will reduce sampling bias and significantly improve the understanding of TB transmission dynamics in households and in community gathering places. For example, TB transmission studies in high TB incidence settings have found that the majority of TB cases occurring concurrently within the same household have non-matching molecular fingerprints. This finding has led to the conclusion that the majority of household TB cases were acquired outside of the household. However, none of those studies have appropriately accounted for within-host heterogeneity, which could have led to missed detection of Mtbc genetic clusters within the household. In addition, despite numerous TB transmission studies, factors that predict TB transmission remain poorly understood. Accounting for within-host Mtbc heterogeneity could improve the detection of pathogen and host related factors that affect transmission. Together, improved understanding of these areas could lead to more accurate identification of transmission networks and disease hotspots, which can then guide interventions to interrupt TB transmission. Moreover, the proposed research could instigate significant changes in the practice of future TB transmission studies by evaluating the impact of accounting for within-host Mtbc heterogeneity on TB transmission inference. The proposed research will address the current gaps in knowledge by incorporating two novel methods for detecting within-host Mtbc heterogeneity: 1) we will conduct whole-genome sequencing (WGS) on early primary culture samples to detect heterogeneous Mtbc strains; and 2) we will perform targeted amplicon-based sequencing of 150 genetic loci important for phylogenetic and resistance prediction. We will use advanced bioinformatic methods to integrate these sources of data on Mtbc heterogeneity. The proposed research will also utilize community-based door-to-door active case finding to minimize sampling bias. These methods will be applied to achieve 2 specific aims: 1) to determine the impact of accounting for within-host heterogeneity of Mtbc strains on inference in a population-based TB transmission study; and 2) to determine more accurately the proportion of household TB cases that are attributable to transmission within the household by conducting a prospective household contact study. We will also determine pathogen and host factors that predict individual and population-level transmission. This project will generate important scientific knowledge of TB transmission and factors that affect transmission, and findings will inform and guide targeted interventions to combat TB epidemics by interrupting the transmission network in local settings.

抽象的 在结核病 (TB) 高发地区，结核病患者通常感染多种菌株 结核分枝杆菌复合体（Mtbc）。尽管存在这一已知事实，但当前的结核病传播研究很大程度上忽略了 宿主内 Mtbc 异质性。我们相信，考虑主机内 Mtbc 异质性将会减少 抽样偏差并显着提高对家庭和社区中结核病传播动态的了解 社区聚会场所。例如，结核病高发地区的结核病传播研究发现 同一家庭内同时发生的大多数结核病例具有不匹配的分子 指纹。这一发现得出的结论是，大多数家庭结核病病例是获得性的 在家庭之外。然而，这些研究都没有适当地解释宿主内部的情况。 异质性，这可能导致漏检家庭内 Mtbc 基因簇。在 此外，尽管进行了大量结核病传播研究，但预测结核病传播的因素仍然很差 明白了。考虑宿主内 Mtbc 异质性可以改善病原体和宿主的检测 影响传播的相关因素。总之，加深对这些领域的了解可能会带来更多 准确识别传播网络和疾病热点，从而指导干预措施 中断结核病传播。此外，拟议的研究可能会引发实践中的重大变化 通过评估宿主内 Mtbc 异质性对未来结核病传播研究的影响 结核病传播推断。 拟议的研究将通过结合两种新方法来解决当前的知识差距 为了检测宿主内 Mtbc 异质性：1）我们将在早期进行全基因组测序（WGS） 原代培养样本以检测异质 Mtbc 菌株； 2）我们将进行基于目标扩增子的 对 150 个对于系统发育和抗性预测很重要的基因位点进行测序。我们将使用先进的 生物信息方法整合这些 Mtbc 异质性数据源。拟议的研究将 还利用基于社区的挨家挨户主动病例发现来最大限度地减少抽样偏差。这些方法将 用于实现 2 个具体目标：1）确定宿主内部异质性的影响 Mtbc 对基于人群的结核病传播研究中的推断产生压力； 2）更准确地确定 通过开展以下活动，可归因于家庭内传播的家庭结核病病例比例 前瞻性家庭接触研究。我们还将确定预测个体的病原体和宿主因素 和人口层面的传播。该项目将产生有关结核病传播的重要科学知识 以及影响传播的因素，研究结果将为防治结核病的有针对性的干预措施提供信息和指导 通过中断当地的传播网络来传播流行病。