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: 10556340
• 负责人: Sanghyuk Sam Shin
• 金额: $ 62.29万
• 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/10556340
• 关键词: Accounting; Affect; Area; Bioinformatics; Botswana; Categories; Cessation of life; Church; Cluster Analysis; Cohort Studies; Collaborations; Communities; DNA; Data; Detection; Development; Disease; Effectiveness; Enrollment; Epidemic; Epidemiology; Exclusion; Future; Genetic; Genotype; Goals; HIV; HIV Infections; HIV/TB; Heterogeneity; High Prevalence; Household; Incidence; Individual; Infection; Integration Host Factors; Interruption; Intervention; Knowledge; 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; case finding; co-infection; combat; detection method; 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 在高结核病（TB）入射率中，患有TB的个体经常感染多种菌株 结核分枝杆菌复合物（MTBC）。尽管这一事实，当前的结核病传播研究基本上忽略了 主持人MTBC异质性。我们认为，占主机MTBC异质性的会计会减少 采样偏见，并显着提高对家庭和家庭中结核病传播动态的理解 社区聚会场所。例如，发现高结核病发病率的结核病传输研究已发现 大多数结核病病例同时发生在同一家庭中都有不匹配的分子 指纹。这一发现得出了结论，即大多数家庭结核病案件均被收购 在家庭外。但是，这些研究都没有适当地解释 异质性，可能导致失踪的家庭中MTBC遗传簇的发现。在 此外，尽管进行了大量结核病的传播研究，但预测结核病传播的因素仍然很差 理解。占主宿内MTBC异质性的情况可以改善病原体的检测和宿主的检测 影响传播的相关因素。共同提高对这些领域的了解可能会导致更多 准确鉴定传输网络和疾病热点，然后可以将干预措施引导到 中断结核病传输。此外，拟议的研究可能会促进实践的重大变化 通过评估宿主内部MTBC异质性对未来结核病传输研究的影响 结核病传输推断。 拟议的研究将通过合并两种新方法来解决知识中当前的知识差距 用于检测主托内MTBC异质性：1）我们将在早期进行全基因组测序（WGS） 原代培养样品以检测异质MTBC菌株； 2）我们将执行基于扩增的目标 对系统发育和抗性预测至关重要的150个遗传基因座的测序。我们将使用高级 生物信息学方法以整合MTBC异质性的数据来​​源。拟议的研究将 还利用基于社区的门到门的活动病例查找来最大程度地减少采样偏差。这些方法将 应用于实现2个特定目标：1）确定会计在主宿内异质性的影响 MTBC菌株在基于人群的结核病传播研究中推断； 2）更准确地确定 通过进行的家庭结核病案件的比例 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 和人口级传播。该项目将对结核病传播产生重要的科学知识 以及影响传播的因素，调查结果将告知和指导针对性的干预措施以对抗结核病 通过在本地设置中中断传输网络来流行。