Bacteria and Host in TB Transmission

摘要 遏制结核病传播的最有效方法是将控制工作集中在地点 通过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严重低估，因为混合感染是 普通和继发性病例可能由具有传播优势的少数人群感染；因此 从指示病例分离的结核分枝杆菌(Mtb)菌株与继发病例之间的不匹配 病例不排除家庭传播。我们还假设，宿主的免疫和病理 结核分枝杆菌对结核分枝杆菌菌株的反应及不同菌株对气雾化胁迫的生存能力 影响传输潜力。在这里，我们建议研究结核病在家庭内的传播特征， 细菌分离物及其与宿主的相互作用、帮助或允许的先天和获得性免疫 传播性。为了解决这些假设，我们将在以下时间进行回顾和前瞻性队列研究 巴西和乌干达利用巴西十多年的家庭接触研究(2004年至今)，由 国际传染病研究合作(ICIDR)和结核病研究股 (TBRU)，以及我们研究团队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对共同流行和偶发的结核病病例负责 最初似乎在基因上与同一家庭内的指标性病例不同。2)调查内部 巴西和乌干达家庭中传播型和非传播型结核分枝杆菌的体外免疫表型 对艾滋病毒状况进行分层。3)表征已知的人的先天和获得性免疫反应 家庭接触高传播和低传播分离株以及艾滋病毒感染的影响。4)识别 结核分枝杆菌基因的组成部分，有助于细菌在气溶胶中存活。5)细菌因素调查 寄主对高传播性和低传播性分离物反应的潜在差异。总而言之，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.