HIV-TB Co-infection: Tracking TB emergence after asymptomatic (latent) infection

HIV-TB 合并感染：追踪无症状（潜伏）感染后结核病的出现

基本信息

批准号：
8706278
负责人：
Philana Ling Lin
金额：
$ 67.93万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-15 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8706278
关键词：
Address Anatomy Animals Area Bacteria Bar Codes Cause of Death Cessation of life Characteristics Clinical Data Disease Emergency Situation Equilibrium Figs - dietary Grant Granuloma Growth HIV HIV Infections Healthcare Human Immune Immune response Immunologics Individual Infection Infection Control Inflammation Lead Lesion Location Macaca Maps Methods Modality Modeling Molecular Mycobacterium tuberculosis NIH Program Announcements Nature Outcome Patients Pattern Pharmaceutical Preparations Positron-Emission Tomography Predisposition Process Relapse Residual state Rest Risk Risk Factors SIV Site Sum Symptoms T cell response Time Tuberculosis Ursidae Family Vaccines Viral Viral Load result X-Ray Computed Tomography active method base clinically significant global health high risk improved in vivo imaging killings latent infection molecular imaging mycobacterial nonhuman primate pathogen public health relevance pulmonary granuloma response tool

项目摘要

DESCRIPTION (provided by applicant): HIV is the most common risk factor for the emergence of active tuberculosis (TB) after previously controlled infection (latent infection). Our data suggest that tuberculous granulomas in a single host are independent and dynamic such that clinical outcome is the sum result of these interactions. Our overarching hypothesis is that each lesion bears its own risk of reactivation that is dependent on immunologic, mycobacterial and viral (HIV) interactions. We will focus on two types of asymptomatic, paucibacillary infection commonly disrupted by HIV infection, classic latent infection that occurs after recent infection (i.e., HIV induced reactivaton) and controlled infection after short course treatment for active TB (i.e., HIV driven relapse). These studies will involve the non- human primate model in which M. tuberculosis and SIV (a surrogate to HIV) infection is similar to humans. In aim 1, we will characterize the process of reactivation among CD4 depleted and SIV infected animals with latent infection. We will use bar-coded M. tuberculosis strains, in vivo imaging (PET CT) and molecular methods to detect granuloma-specific growth and killing to examine the lesional conditions that lead to reactivation compared to latent controls in the non-human primate model. We will characterize lesion specific viral load, bacterial burden and immune responses to determine what factors lead to lesional reactivation. In aim 2, we will develop a model for relapse in which asymptomatic, paucibacillary disease occurs after short course treatment for active TB. We will identify bacterial reservoirs of relapse, track bacterial relapse during SIV-Mtb co-infection and determine the lesional risk factors of relapse. In both aims 1 and 2, we will generate a road map of reactivation/relapse, identify the lesions at greatest risk and dissect the immunologic, mycobacterial and viral interactions that contribute to their risk of reactivation/relapse on a lesional level. Many of these findings, especially PET CT characterizations, are likely to be directly translatable to humans. Results of these studies will ultimately lead to better drugs strategies (targeting sites of residual bacteria at high risk of reactivation or relapse) and immun modulating modalities (either as vaccine or supplement to drug treatment).

描述（由申请人提供）： HIV是先前控制感染（潜在感染）后活跃结核病（TB）出现的最常见危险因素。我们的数据表明，单个宿主中的结核性肉芽肿是独立且动态的，因此临床结果是这些相互作用的总和。我们的总体假设是，每个病变都有其自身重新激活的风险，这取决于免疫，分枝杆菌和病毒（HIV）相互作用。我们将重点关注两种类型的无症状的，paucibail的感染，通常受到HIV感染的破坏，经典的潜在感染，这些感染在最近感染后发生（即HIV诱导的反应性反应量）和对活性结核的短期治疗后发生的受控感染（即HIV驱动的复发）。这些研究将涉及非人类灵长类动物模型，其中结核分枝杆菌和SIV（替代HIV）感染与人类相似。在AIM 1中，我们将表征CD4耗尽和SIV感染潜在感染的动物的重新激活过程。我们将使用条形编码的结核分枝杆菌菌株，体内成像（PET CT）和分子方法来检测肉芽肿特异性生长并杀死，以检查与非人类灵长类动物模型中潜在的对照相比，导致重新激活的病变条件。我们将表征病变特异性病毒载荷，细菌负担和免疫反应，以确定哪些因素导致病变重新激活。在AIM 2中，我们将开发一个模型以复发，其中无症状的，无症状的paucibacillary疾病是在短期治疗活动TB后发生的。我们将确定复发的细菌储层，在SIV-MTB共感染期间跟踪细菌复发，并确定病变的危险因素。在AIM 1和2中，我们将生成一个重新激活/复发的路线图，确定风险最大的病变，并剖析免疫，分枝杆菌和病毒相互作用，从而有助于其在耶和华水平上重新激活/复发的风险。这些发现中的许多，尤其是PET CT特征，可能直接翻译成人类。这些研究的结果最终将导致更好的药物策略（靶向具有高重新激活或复发风险的残留细菌部位）和免疫调节方法（作为疫苗或药物治疗补充）。