Macaque model of TB/AIDS co-infection via natural routes of exposure

描述（由申请人提供）：结核病（TB）和获得性免疫缺陷综合征（AIDS）共同导致全世界每年超过400万人死亡。第三世界的公共卫生系统由于这些流行病的双重袭击而面临着严重的灾难。结核分枝杆菌（Mtb）的多重耐药（MDR）和广泛耐药（XDR）菌株的出现、卡介苗（BCG）疫苗未能控制TB的传播以及我们无法开发有效的抗TB药物使这种情况恶化。人类免疫病毒（HIV）诱导的免疫抑制是结核病复发的重要因素;可能有四分之一的HIV病例继续发展为活动性结核病。全世界的艾滋病形势同样令人沮丧。对抗艾滋病的一线候选疫苗在临床试验中失败了。我们仍然没有完全了解艾滋病发病机制和相关的保护。甚至抗逆转录病毒疗法的出现也未能对这种情况产生影响。迫切需要新的药物和疫苗来对抗结核病和艾滋病。结核病、艾滋病和结核病-艾滋病合并感染的健全动物模型将是开发和测试针对这些疾病的疫苗和药物的战略的关键部分。在感染猴免疫病毒（SIV）的恒河猴中，已经可以非常好地模拟艾滋病。这些猕猴在感染后外周血和各种淋巴组织中的CD 4 + T细胞水平迅速下降，并发展为以严重免疫缺陷为特征的慢性至急性AIDS。用Mtb感染猕猴产生多种结果，包括原发性暴发性TB、慢性、缓慢进行性TB或潜伏感染，从而准确地再现了人类TB的宿主驱动的多样性。我们最近已经证明了用高剂量或低剂量的雾化结核分枝杆菌感染恒河猴的能力，分别产生活动性肺结核和潜伏性疾病。通过气溶胶途径感染猕猴的能力将使我们能够尽可能接近自然疾病的结核病模型。在这个提议中，我们想联合收割机我们最近开发的基于气溶胶的恒河猴结核病模型，以前存在的SIV感染模型在同一物种中，为了研究SIV和Mtb之间的共感染的临床，免疫学，分子和病理学参数。因此，本研究的目的在于达成以下的研究目标：1。建立了M.结核病/SIV共同感染恒河猴，模拟两种病原体的自然感染途径。2.确定恒河猴是否潜伏感染低剂量的M。在静脉感染SIV后，结核病以显著不同的方式重新激活为活动性疾病。公共卫生相关性：结核病（TB）和获得性免疫缺陷综合征（AIDS）是人类最具破坏性的两种传染病，每年一起导致近400万人死亡。由于许多国家公共卫生系统的崩溃、艾滋病和结核病之间明显的协同作用、卡介苗（抗结核疫苗）和艾滋病疫苗在管道中的惊人失败以及耐药性，危机进一步恶化。艾滋病是由人类免疫缺陷病毒（HIV）引起的，而结核病是由结核分枝杆菌（Mtb）引起的。感染猴免疫缺陷病毒（SIV）的恒河猴是人类艾滋病的精确模型。这一模型有助于发展我们目前对艾滋病发病机制和病理学的理解。人们对结核病的非人灵长类动物模型也重新产生了兴趣。这些动物准确地模拟了临床结核病的各个阶段，并描绘了人类结核病病理学的整个谱。我们最近将恒河猴暴露于高剂量的M。肺结核气溶胶这导致了严重的肺结核的发展。另一方面，恒河猴暴露于低剂量的Mtb气溶胶导致潜伏感染。我们相信，用结核分枝杆菌的传染性气溶胶感染NHP的能力代表了一个重大的进步，因为它使我们能够在自然环境中研究这种疾病。因此，本研究的目的在于达成以下的研究目标：1。在恒河猴中建立Mtb/SIV共感染模型，模拟两种病原体的自然感染途径。2.确定是否恒河猴潜伏感染低剂量气溶胶结核分枝杆菌重新激活活动性疾病在一个显着不同的方式，静脉注射SIV感染。

DESCRIPTION (provided by applicant): Tuberculosis (TB) and Acquired Immune Deficiency Syndrome (AIDS), together, lead to the death of more than four million people annually, world-wide. The public health system in third world faces unmitigated disaster due to the twin assault from these pandemics. The emergence of Multi Drug-Resistant (MDR) and Extensively Drug-Resistant (XDR) strains of Mycobacterium tuberculosis (Mtb), the failure of Bacille Calmette- Guerin (BCG) vaccine to control the spread of TB, and our inability to develop effective anti-TB drugs has worsened this situation. Human Immune Virus (HIV)-induced immuno-suppression is a substantial contributor to TB reactivation; perhaps one-quarter of all HIV cases go on to develop active TB. The world-wide AIDS situation is equally gloomy. The frontline candidate vaccines against AIDS have failed in clinical trials. We still do not completely understand mechanisms of AIDS pathogenesis and correlates of protection. Even the advent of Anti-retroviral therapy (ART) has not been able to impact this situation. New drugs and vaccines are urgently needed to combat both the TB and AIDS. Robust animal models of TB, AIDS and TB-AIDS co- infection will be a crucial part of the strategy to develop and test vaccines and drugs against these diseases. It has been possible to model AIDS extremely well in rhesus macaques infected with Simian immune Virus (SIV). These macaques undergo a rapid decline in the CD4+ T cell levels in peripheral blood and various lymphoid tissues following infection, and develop chronic to acute AIDS characterized by severe immune deficiency. Infection of macaques with Mtb produces a variety of outcomes, including primary fulminate TB, chronic, slowly progressive TB, or latent infection, thus accurately recapitulating the host-driven diversity of human TB. We have recently demonstrated the capability to infect rhesus macaques with a high- or low-dose of aerosolized Mtb, producing active pulmonary TB and latent disease, respectively. The ability to infect macaques with Mtb via the aerosol route will allow us to model TB as closely as possible to natural disease. In this proposal, we would like to combine our recently developed aerosol-based model of TB in rhesus macaques, to the previously existing SIV infection model in the same species, in order to study the clinical, immunological, molecular and pathological parameters of co-infection between SIV and Mtb. Consequently, the proposal aims to achieve the following research objectives: 1. Establish a model of M. tuberculosis/SIV co- infection in rhesus macaques, mimicking the natural route of infection for both pathogens. 2. Determine if rhesus macaques latently infected with low-dose aerosols of M. tuberculosis reactivate to active disease in significantly different fashion, following intravenous infection with SIV. PUBLIC HEALTH RELEVANCE: Tuberculosis (TB) and Acquired Immune Deficiency syndrome (AIDS) are two of the most devastating infectious diseases of mankind, together resulting in close to four million annual deaths. The crisis has further worsened due to a collapse of public health system in many nations, the apparent synergy between AIDS and TB, the spectacular failure of BCG (the anti-TB vaccine) and AIDS vaccines in the pipeline, and drug resistance. AIDS is caused by Human Immunodeficiency Virus (HIV), while TB is caused by Mycobacterium tuberculosis (Mtb). Rhesus macaques infected with Simian Immunodeficiency Virus (SIV) are an accurate model of human AIDS. This model has been instrumental in developing our current understanding of AIDS pathogenesis and pathology. There is also a renewed interest in the nonhuman primate model of TB. These animals accurately model various phases of clinical TB, and portray the entire spectrum of the pathology of human TB. We recently exposed rhesus macaques to high dose of M. tuberculosis aerosols. This led to the development of significant pulmonary TB. Exposure of rhesus macaques to a low dose of Mtb aerosols on the other hand, led to latent infection. We believe that the ability to infect NHP's with infectious aerosols of Mtb represents a significant advance, since it allows us to study the disease in a natural context. Consequently, the proposal aims to achieve the following research objectives: 1. Establish a model of Mtb/SIV co-infection in rhesus macaques, mimicking the natural route of infection for both pathogens. 2. Determine if rhesus macaques latently infected with low-dose aerosols of Mtb reactivate to active disease in a significantly different fashion, following intravenous SIV infection.