Determinants of TB control, relapse and reinfection

结核病(TB)的病原体结核分枝杆菌(Mtb)仍然是一个严重的全球性问题。 健康问题。结核病是多方面的，但这种疾病的一个主要临床和微生物学特征是能够 能抵抗宿主免疫系统和有效的化疗药物的完全清除 生长抑制活性。面对免疫和抗生素压力的这种坚持不懈奠定了几个 结核病的重要方面，包括1)潜伏的结核病感染的存在，以及在 LTBI控制的免疫失败及其在活动性结核病发生中的作用；2)结核病病程延长 抗生素治疗，需要6个月的多种药物治疗才能达到可靠的临床治愈。而不是 在所有接受治疗的对象中彻底根除细菌，结核病化疗后的治愈现在是 被认为是一种抗生素诱导的少杆菌状态，在这种状态下预防复发部分依赖于 对宿主因素知之甚少。调节这两种相互关联类型的寄主和细菌的决定因素 坚持不懈只被部分理解，这是Tri-I-TBRU旨在填补的一个知识空白。我们提出了一套3个 交叉项目和3个核心都侧重于少杆菌结核病问题的不同方面，都是 治疗和LTBI。这些项目将使用我们临床站点的结核病队列的样本和临床数据，网址为 在海地太子港的盖斯基奥，检查免疫学、微生物组、转录组、药代动力学、 以及影响或预测结核病的少杆菌状态和转折点的遗传因素 活动性传染性感染。这些人体研究将与一种新的老鼠模型进行比较和对比 这将使我们能够检验关于宿主和细菌的机械假说 少杆菌病的决定因素。这项工作将由一个高度合作的团队进行 几年来合作良好的调查人员。

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), continues to be a severe global health problem. TB is multifaceted, but a central clinical and microbiologic feature of the disease is the ability of Mtb to resist complete elimination, both by the host immune system and by chemotherapeutic agents with potent growth inhibitory activity. This persistence in the face of immunologic and antibiotic pressure underlies several important facets of TB disease, including 1) the existence of latent tuberculosis infection (LTBI) and, in the setting of immunologic failure of LTBI control, its role in the genesis of active TB and 2) the prolonged course of TB antibiotic therapy, which requires 6 months of multidrug therapy to achieve reliable clinical cure. Rather than producing complete bacterial eradication in all treated subjects, cure following TB chemotherapy is now understood to be an antibiotic induced paucibacillary state in which prevention of relapse depends in part on poorly understood host factors. The host and bacterial determinants that mediate these two interrelated types of persistence are only partially understood, a knowledge gap the Tri-I-TBRU aims to fill. We propose a set of 3 intersecting projects and 3 cores all focused on different facets of the problem of paucibacillary TB, both post treatment and LTBI. The projects will use samples and clinical data from TB cohorts at our clinical site at GHESKIO in Port Au Prince Haiti, to examine the immunologic, microbiomic, transcriptomic, pharmacokinetic, and genetic factors that influence or predict the transition points between paucibacillary states of TB disease and active transmissible infection. These human studies will be compared and contrasted with a new mouse model of paucibacillary infection that will allow us to test mechanistic hypotheses about the host and bacterial determinants of paucibacillary disease. This work with be conducted by a team of highly collaborative investigators who have who have worked well together for several years.