US BRAZIL COLLABORATION ON IMMUNITY AND BIOMARKERS IN TUBERCULOSIS

描述（由申请人提供）：结核病（TB）作为一个主要的全球公共问题引起了人们的关注，导致大量资源投入到研究和控制活动中。尽管取得了重大的科学进展，但缺乏关键的转化工具。其中最主要的是协助制定预防和管理结核病的新方法和模式的生物标志物。它们的发展受到阻碍，部分原因是由于对宿主-细菌关系的了解有限。目前的提案扩大了美国-巴西合作的重点，以解决更基本的问题，如宿主对结核分枝杆菌（Mtb）感染的易感性、近期结核感染的免疫动力学以及可能在治疗复发中起作用的细菌因素。因此，该项目的高影响力转化目标是发现对结核病预防和治疗具有临床重要性的生物标志物。具体目标是：1。目的：探讨结核分枝杆菌感染耐药和易感的免疫学基础及相关生物标志物。这些结果可能为开发新的治疗方法、结核病疫苗和针对先天免疫的佐剂提供新的概念和生物标志物。2. 阐明结核分枝杆菌感染演变的免疫动力学，并在临床样本中发现可测量的生物标志物，以准确识别近期结核分枝杆菌感染和/或活跃的结核分枝杆菌复制，从而识别结核病高危人群。3. 以确定是否与复发相关的结核分枝杆菌分离株1)对抗生素的亚临床耐药性低于或接近临床断点，2)根据BACTEC测定对抗生素的耐受性更强，或3)显示“协同作用丧失”表型。此外，为了确定与这些表型相关的遗传机制是否包括1)embB突变，2)泵突变，如iniA， 3)并发现其他未知的机制。这些研究将描述与治疗失败相关的结核分枝杆菌的表型和基因型生物标志物。感染这种分离株的结核病患者可能需要其他治疗方法。相关性（见说明）：结核病是一个重大的全球公共卫生问题。现有的预防和控制结核病的方法都失败了。这项研究将提供对开发控制结核病的改进工具和方法至关重要的生物标志物。

DESCRIPTION (provided by applicant): Tuberculosis (TB) has attracted attention as a leading global public problem resulting in the commitment of substantial resources to research and control activities. Although significant scientific advances have ensued, key translational tools are lacking. Chief among these are biomarkers to assist in developing new approaches and modalities for the prevention and management of TB. Their development has been retarded, in part, is because of limited understanding of the host-bacterial relationship. The current proposal broadens the focus of the U.S.-Brazil collaboration to address more fundamental issues concerning host susceptibility to Mycobacterium tuberculosis (Mtb) infection, the immunodynamics of recent TB infection, and bacterial factors that may play a role in treatment relapse. The high impact translational goal of this program, then, is to discover biomarkers of clinical importance to the prevention and treatment of TB. The Specific Aims are 1 .To determine the immunologic basis for resistance and susceptibility to Mtb infection and the correlate biomarkers. The results may provide new concepts as well as biomarkers relevant to the development of novel treatments, TB vaccines and adjuvants that target innate immunity. 2. to elucidate the immunodynamics of evolving Mtb infection and to discover measurable biomarkers in clinical samples that could accurately identify recent Mtb infection and/or active Mtb replication, thereby identifying persons at high risk of TB. 3. to determine whether Mtb isolates associated with relapse 1) have sub clinical resistance below or around clinical breakpoints for the antibiotic, 2) are more tolerant of antibiotics as measured by BACTEC assays or 3) display a "loss-of-synergy" phenotype. Further, to determine whether genetic mechanisms associated with these phenotypes include 1) embB mutations, 2) pump mutations such as iniA 3) and to discover other as yet unknown mechanisms. These studies will characterize phenotypic and genotypic biomarkers of Mtb that are associated with treatment failure. TB patients infected with such isolates may require alternative approaches to treatment. RELEVANCE (See instructions): TB is a major global public health concern. The available approaches to prevention and control of TB have failed. This research will provide biomarkers that will be essential to develop improved tools and approaches to control TB.