Bacteria and Host in TB Transmission

摘要 通过将控制工作集中在场所，将最有效地实现遏制结核病传播 以及开发针对细菌传播的新药和疫苗。我们 假设家庭结核病传播被大大低估，因为混合感染 普通和继发病例可能由具有传播优势的少数人群感染;因此， 从指示病例中分离的结核分枝杆菌（Mtb）菌株与继发性 不排除家庭传播。我们还假设宿主的免疫和病理 对Mtb分离株的反应以及不同Mtb分离株在气溶胶化的压力下强烈存活的能力 影响传播潜力。在这里，我们建议研究家庭内结核病传播的特点， 细菌分离物及其与宿主先天性和适应性免疫的相互作用， 可传递性为了解决这些假设，我们将进行回顾性和前瞻性队列研究， 在巴西和乌干达，利用由联合国艾滋病毒/艾滋病联合规划署资助的十多年的巴西家庭接触研究（2004年至今）， 国际传染病研究合作组织（ICIDR）和结核病研究单位 （TBRU），以及我们研究团队之间20多年的合作研究。我们的具体目标是：（1） 确定家庭传播在多大程度上是造成同时流行和偶发结核病例的原因， 最初似乎在遗传上与同一家庭中的指示病例不同。2)为了调查 巴西和乌干达家庭中传播与非传播结核分枝杆菌分离株的体外免疫表型 艾滋病病毒感染状况。3)描述已知先天性和适应性免疫反应的人， 家庭暴露于高和低传播隔离物以及艾滋病毒感染的影响。4)识别 帮助细菌在气溶胶中存活的Mtb基因组分。5)探讨细菌因素 宿主对高和低传播分离株的反应存在潜在差异。这些研究将 提供新的传播模式和新的干预目标。

ABSTRACT Halting tuberculosis (TB) transmission will be most efficiently achieved by focusing control efforts on sites of high transmission and by developing new drugs and vaccines that target bacterial transmission. We hypothesize that household TB transmission is dramatically under-estimated because mixed infections are common and secondary cases may be infected by minor populations having a transmission advantage; ergo that mismatch between the Mycobacterium tuberculosis (Mtb) strain isolated from the index case and secondary case does not preclude household transmission. We also hypothesize that the host immune and pathological response to Mtb isolates and the ability of different Mtb isolates to survive the stress of aerosolization strongly impacts transmission potential. Here, we propose to study characteristics of TB transmission within households, the bacterial isolate and its interaction with the host innate and adaptive immunity that aid or are permissive of transmissibility. To address these hypotheses, we will conduct retrospective and prospective cohort studies in Brazil and in Uganda leveraging over a decade of household contact studies in Brazil (2004-date) funded by the International Collaboration for Infectious Diseases Research (ICIDR) and the Tuberculosis Research Unit (TBRU), and over 20 years of collaborative research among our study team. Our Specific Aims are: 1) To determine the extent to which household transmission is responsible for co-prevalent and incident TB cases that initially appear to be genetically distinct from index cases within the same household. 2) To investigate the in vitro immune phenotype of transmitted versus not-transmitted Mtb isolates in Brazilian and Ugandan households stratifying for HIV status. 3) To characterize the innate and adaptive immune response in persons with known household exposure to high and low transmission isolates and the impact of HIV infection. 4) To identify the component of Mtb genes that aid in bacterial survival in aerosols. 5) To investigate the bacterial factors underlying divergence in the host response to high and low transmission isolates. Together, these studies will provide new paradigms for transmission and novel targets for intervention.