Reactivated tuberculosis in SIV-infected cynomolgus macaques

感染 SIV 的食蟹猴体内结核病重新激活

基本信息

批准号：
8022929
负责人：
Joshua T. Mattila
金额：
$ 5.22万
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：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2011-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects one third of the worlds population. Tuberculosis is a deadly disease that kills more young people than any other infectious disease. Fortunately, most people mount immune responses that contain the infection and they maintain the infection in a subclinical state referred to as latency with only a 10% lifetime risk of experiencing reactivation. A broad number of host factors are responsible for maintenance of latency. Host immune cells, including macrophages and lymphocytes, form nodular structures called granulomas that wall off bacteria and effectively prevent dissemination. A number of other factors, including cytokines and chemokines, are required to coordinate cellular activities maintain the granuloma integrity. Infection with human immunodeficiency virus (HIV) is the most significant risk factor for development of active or reactivation TB. HIV infected individuals with latent TB have dramatically increased odds of reactivation, with a 10% annual (versus 10% lifetime) risk of experiencing reactivated TB. Additionally, infection with M. tuberculosis results in increased HIV replication. Thus, individuals who are coinfected experience a series of negative events, most of which remain poorly understood, that greatly increase morbidity and mortality. While M. tuberculosis infection can be treated with drugs, the rise of multidrug resistance in areas of the world with high incidence of HIV is a matter of great concern. We have developed a nonhuman primate model using cynomolgus macaques that accurately describes the pathology of latent TB in humans. We will use the cynomolgus macaques to coinfected with TB and simian immunodeficiency virus (SIV), an HIV-like virus, to explore the hypothesis that reactivation of latent TB can be predicted by changes in immune status including lymphocyte numbers and cytokine expression. Our purpose is to understand why HIV-related changes in immune status cause reactivated TB, even in the early stages of infection, and to clarify why coinfection dramatically enhances pathogenicity of HIV and M. tuberculosis infection. We anticipate the results of these studies will also uncover clinically relevant immune markers that may hearld reactivated TB and provide useful diagnostic tools for clinicans treating HIV- infected individuals.

描述（由申请人提供）：结核分枝杆菌是结核病（TB）的病原体，感染世界三分之一的人口。结核病是一种致命的疾病，比任何其他传染病杀死的年轻人都多。幸运的是，大多数人会发起包含感染的免疫反应，并将感染维持在亚临床状态（称为潜伏期），一生中仅有 10% 的重新激活风险。许多主机因素都会导致延迟的维持。宿主免疫细胞，包括巨噬细胞和淋巴细胞，形成称为肉芽肿的结节结构，可以隔离细菌并有效防止传播。需要许多其他因素，包括细胞因子和趋化因子来协调细胞活动以维持肉芽肿的完整性。人类免疫缺陷病毒（HIV）感染是形成活动性或再激活性结核病的最重要危险因素。患有潜伏性结核病的 HIV 感染者重新激活的几率大大增加，每年（相对于一生中 10%）出现重新激活结核病的风险为 10%。此外，结核分枝杆菌感染会导致艾滋病毒复制增加。因此，同时感染的个体会经历一系列负面事件，其中大多数仍知之甚少，这大大增加了发病率和死亡率。虽然结核分枝杆菌感染可以用药物治疗，但在世界艾滋病毒高发地区，多重耐药性的上升是一个令人高度关注的问题。我们利用食蟹猴开发了一种非人类灵长类动物模型，可以准确描述人类潜伏结核病的病理学。我们将使用同时感染结核病和猿猴免疫缺陷病毒（SIV）（一种艾滋病毒样病毒）的食蟹猴，探索可以通过免疫状态（包括淋巴细胞数量和细胞因子表达）的变化来预测潜伏结核病重新激活的假设。我们的目的是了解为什么艾滋病毒相关的免疫状态变化会导致结核病重新激活，甚至在感染的早期阶段也是如此，并阐明为什么合并感染会显着增强艾滋病毒和结核分枝杆菌感染的致病性。我们预计这些研究的结果还将揭示临床相关的免疫标志物，这些标志物可能会发现结核病的再激活，并为治疗艾滋病毒感染者的临床医生提供有用的诊断工具。