Reactivated tuberculosis in SIV-infected cynomolgus macaques

感染 SIV 的食蟹猴体内结核病重新激活

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/8022929
• 关键词: Antigens; Area; Bacteria; Cause of Death; Cells; Cellular Structures; Communicable Diseases; Development; Diagnostic; Disease; Epidemic; Equilibrium; Event; Genetic; Granuloma; HIV; Health; Human; Immune; Immune response; Immunologic Markers; Incidence; Individual; Infection; Integration Host Factors; Laboratory Animals; Life; Lymphocyte; Lymphocyte Count; Macaca; Maintenance; Modeling; Monkeys; Morbidity - disease rate; Multi-Drug Resistance; Mycobacterium tuberculosis; Pathogenicity; Pathology; Pharmaceutical Preparations; Physiological; Population; Process; Research; Risk; Risk Factors; SIV; Series; Staging; Structure; T-Lymphocyte; Tuberculosis; Virus; Virus Diseases; Virus Replication; chemokine; clinically relevant; cytokine; experience; killings; latent infection; lifetime risk; macrophage; mortality; nonhuman primate; prevent; response; tool

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(申请人提供)：结核分枝杆菌，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，死亡的年轻人比其他任何传染病都多。幸运的是，大多数人的免疫反应包含感染，他们将感染保持在一种被称为潜伏期的亚临床状态，一生中经历重新激活的风险只有10%。许多主机因素负责延迟的维护。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，将细菌隔开，有效地防止传播。许多其他因素，包括细胞因子和趋化因子，需要协调细胞活动来维持肉芽肿的完整性。感染人类免疫缺陷病毒(HIV)是发展成活动性或再活动性结核病的最重要的风险因素。患有潜伏性结核病的艾滋病毒感染者极大地增加了重新激活的几率，每年有10%的风险(而不是终生的10%)经历重新激活的结核病。此外，感染结核分枝杆菌会导致艾滋病毒复制增加。因此，合并感染的人经历了一系列负面事件，其中大多数仍然鲜为人知，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，多重耐药性的增加是一个非常令人关切的问题。我们利用食蟹猴开发了一种非人类灵长类动物模型，准确地描述了人类潜伏性结核病的病理。我们将利用食蟹猴与结核病和类似艾滋病毒的猴免疫缺陷病毒(SIV)混合感染，来探索可以通过免疫状态的变化(包括淋巴细胞数量和细胞因子表达)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HIV相关的免疫状态的变化会导致重新激活的结核病，甚至在感染的早期阶段，并阐明为什么混合感染显著增强了HIV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发现临床上相关的免疫标记物，这些标记物可能会导致重新激活的结核病，并为临床医生治疗艾滋病毒感染者提供有用的诊断工具。

项目成果

Granzyme B-expressing neutrophils correlate with bacterial load in granulomas from Mycobacterium tuberculosis-infected cynomolgus macaques.

• DOI: 10.1111/cmi.12428
• 发表时间: 2015-08
• 期刊: Cellular microbiology
• 影响因子: 3.4
• 作者: Mattila JT;Maiello P;Sun T;Via LE;Flynn JL
• 通讯作者: Flynn JL