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，导致大量资源用于研究和控制活动。虽然随后取得了重大的科学进步，但缺乏关键的翻译工具。其中最主要的是生物标志物，以协助开发新的方法和模式，预防和管理结核病。它们的发育受到阻碍，部分原因是对宿主与细菌关系的了解有限。目前的提议扩大了美国的关注点-巴西的合作，以解决有关宿主对结核分枝杆菌（Mtb）感染的易感性，最近结核病感染的免疫动力学，以及可能在治疗复发中发挥作用的细菌因素等更根本的问题。因此，该计划的高影响转化目标是发现对预防和治疗结核病具有临床重要性的生物标志物。本研究的具体目的是：1 .探讨结核分枝杆菌感染的免疫学基础及相关生物标志物。这些结果可能为开发针对先天免疫的新型治疗方法、结核疫苗和佐剂提供新的概念和生物标志物。2.阐明演变中的Mtb感染的免疫动力学，并发现临床样品中可测量的生物标志物，其可以准确地鉴定最近的Mtb感染和/或活跃的Mtb复制，从而鉴定处于TB高风险的人。3.以确定与复发相关的Mtb分离株是否1）具有低于或接近抗生素临床断点的亚临床抗性，2）如通过BACTEC测定所测量的对抗生素更耐受，或3）显示“协同作用丧失”表型。此外，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。这些研究将表征与治疗失败相关的Mtb表型和基因型生物标志物。感染此类分离株的结核病患者可能需要替代治疗方法。相关性（见说明）：结核病是一个主要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。这项研究将提供生物标志物，这对于开发控制结核病的改进工具和方法至关重要。

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.