Dissecting the pathogenesis of HIV-TB Immune reconstitution inflammatory syndrome

尽管全球医疗保健取得了重大进展，但估计仍有150万人死亡，新增1000万人 2018年结核病病例数。近100万艾滋病毒携带者患上了结核病。共同-- 感染艾滋病毒和结核病与高发病率和死亡率以及使用结核病药物和抗结核药物治疗有关 逆转录病毒(ART)疗法现在普遍可用。结核病药物治疗后抗逆转录病毒治疗可改善长期疗效 存活，特别是那些免疫系统受到严重抑制而不受艾滋病毒感染的人。标牌 疾病症状在治疗开始后不久就会改善，但在许多情况下，疾病可能会复发和 临床上看起来更糟，因为免疫系统正在通过抗逆转录病毒治疗重建。这就是众所周知的结核病- 相关免疫重建炎症综合征(TB-IRIS)，在患者中更常见 治疗前免疫系统受到严重抑制的患者，以及 开始结核病治疗和抗逆转录病毒治疗。关于结核病-IRIS如何或为什么发生以及如何最好地治疗，人们知之甚少 或者甚至阻止它。我们假设TB-IRIS的症状是由两者之间的动态相互作用驱动的 免疫系统，结核分枝杆菌(结核分枝杆菌，引起结核病的细菌)和艾滋病毒 体内受感染的组织，如肺肉芽肿。几乎不知道发生了什么 结核分枝杆菌和艾滋病毒在结核病-IRIS期间相互作用的组织。这项提议将开发一种结核病的动物模型-- 虹膜通过利用我们先前存在的艾滋病毒-结核病联合感染模型，在该模型中，携带SIV-MTB的动物共同- 与人类一样，感染者也要接受结核病药物治疗和抗逆转录病毒治疗。我们将使用复杂的成像技术， 免疫学和微生物学工具，以更好地了解结核病-IRIS是如何和为什么发生的，以及哪些因素可以 预测它的出现。目标1将确定结核病-IRIS在该模型中发生的频率以及结核分枝杆菌和 在治疗过程中，SIV仍留在组织中。我们还将对以下更改执行详细检查 发生在组织中，特别是肺(肉芽肿)和淋巴结通过一系列活体图像 更好地了解导致结核病-IRIS的事件及其预测因素。在目标2中，我们将执行详细的 TB-IRIS期间组织和血液中免疫事件的检测。组织特异性(肺 肉芽肿和淋巴结)免疫反应将与结核分枝杆菌和病毒的数量相关 结合影像表现，以便更好地了解TB-IRIS的病因。我们的短期目标是 在这项建议中，更好地理解结核病-IRIS的发病机制，这些发现最终将导致更好的 治疗和预防结核病-IRIS是我们的长期目标。

Despite major advances in global health care, there were an estimated 1.5 millions deaths and 10 million new cases of tuberculosis (TB) in 2018. Nearly 1 million people living with HIV developed tuberculosis (TB). Co- infection with HIV and TB is associated with high morbidity and mortality and treatment with TB drugs and anti- retroviral (ART) therapy is now universally available. TB drug treatment followed by ART improves long term survival, particularly among those whose immune systems are severely suppressed from HIV infection. Signs and symptoms of disease improve soon after treatment is started but, in many cases, disease can recur and appear clinically worse as the immune system is being re-established from ART. This is known as TB- associated Immune Reconstitution Inflammatory Syndrome (TB-IRIS) and is more common among patients with severely suppressed immune systems before treatment and those who have a short time interval between starting TB treatment and ART. Very little is known about how or why TB-IRIS occurs and how to best to treat or even prevent it. We hypothesize that symptoms of TB-IRIS are driven by the dynamic interaction between the immune system, Mycobacterium tuberculosis (Mtb, the bacteria that causes TB) and HIV deep within infected tissues in the body such as the lung granuloma. Virtually nothing is known about what happens in the tissues where both Mtb and HIV interact during TB-IRIS. This proposal will develop an animal model of TB- IRIS by taking advantage of our pre-existing model of HIV-TB co-infection in which animals with SIV-Mtb co- infection undergo TB drug treatment and ART just like humans. We will use sophisticated imaging, immunology and microbiologic tools to better understand how and why TB-IRIS develops and what factors can predict its emergence. Aim 1 will determine how often TB-IRIS occurs in this model and to what extent Mtb and SIV remain in the tissues during treatment. We will also perform a detailed examination of the changes that occur in the tissues but especially the lungs (granulomas) and lymph nodes through serial in vivo images to better understand the events that lead to TB-IRIS and its predictors. In Aim 2, we will perform a detailed examination of the immunologic events in the tissues and blood during TB-IRIS. Tissue specific (lung granulomas and lymph nodes) immune responses will be correlated with the amount of Mtb bacteria and virus with the imaging findings so that we can better understand the causes of TB-IRIS. Our short term goal is to better understand the pathogenesis of TB-IRIS in this proposal and these findings will ultimately lead to better treatment and prevention of TB-IRIS which is our long term goal.