Reactivated tuberculosis in SIV-infected cynomolgus macaques

描述（由申请人提供）：结核分枝杆菌，结核病（TB）的病原体，感染了世界三分之一的人口。肺结核是一种致命的疾病，比任何其他传染病都要多。幸运的是，大多数人会产生包含感染的免疫反应，并且他们将感染保持在亚临床状态，称为潜伏期，只有10%的终身风险经历重新激活。大量的主机因素负责延迟的维持。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状结构，将细菌隔离并有效地防止传播。许多其他因素，包括细胞因子和趋化因子，需要协调细胞活动，维持肉芽肿的完整性。人类免疫缺陷病毒（HIV）感染是发展为活动性或复发性结核病的最重要危险因素。感染HIV的潜伏性结核病患者复发的几率显著增加，每年复发结核病的风险为10%（而终生为10%）。此外，M.结核病导致艾滋病毒复制增加。因此，合并感染者会经历一系列负面事件，其中大多数仍然知之甚少，大大增加了发病率和死亡率。而M.虽然结核病感染可以用药物治疗，但世界上艾滋病毒高发地区的多药耐药性上升是一个令人极为关切的问题。我们使用食蟹猴开发了一种非人灵长类动物模型，该模型准确描述了人类潜伏性TB的病理学。我们将使用食蟹猴共感染结核病和猴免疫缺陷病毒（SIV），一种HIV样病毒，探索的假设，潜伏性结核病的再激活可以预测的免疫状态的变化，包括淋巴细胞数量和细胞因子的表达。我们的目的是了解为什么HIV相关的免疫状态变化会导致结核病复发，即使是在感染的早期阶段，并阐明为什么合并感染会显著增强HIV和M的致病性。肺结核感染。我们预计这些研究的结果也将揭示可能导致结核病复发的临床相关免疫标志物，并为治疗HIV感染者的临床医生提供有用的诊断工具。

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.