Dissecting the pathogenesis of HIV-TB Immune reconstitution inflammatory syndrome

剖析 HIV-TB 免疫重建炎症综合征的发病机制

• 批准号: 10451735
• 负责人: JoAnne L. Flynn
• 金额: $ 76.37万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-17 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10451735
• 关键词: Address; Adverse effects; Aftercare; Animal Model; Animals; Anti-Retroviral Agents; Antitubercular Agents; Autopsy; Bacteria; Biological Markers; Blood; CD4 Lymphocyte Count; Cells; Cessation of life; Characteristics; Clinical; Collaborations; Complex; Country; Data; Development; Disease; Disease model; Early treatment; Event; Goals; Granuloma; HIV; HIV Infections; HIV/TB; Healthcare; Heterogeneity; Hospitalization; Human; Image; Immune; Immune response; Immune system; Immunologics; Immunology; Improve Access; Incidence; Infection; Inflammation; Inflammatory; Knowledge; Lead; Measures; Medical Research; Microbiology; Mission; Modality; Modeling; Morbidity - disease rate; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Nature; Pathogenesis; Pathology; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Positron-Emission Tomography; Prednisone; Prevention; Prevention strategy; Process; Research Infrastructure; Research Personnel; Resources; Risk; SIV; Signs and Symptoms; Site; Symptoms; Syndrome; Technology; Therapeutic; Time; Tissues; Tuberculosis; United States National Institutes of Health; Vaccines; Virus; adaptive immune response; antiretroviral therapy; clinical predictors; co-infection; global health; high risk; human disease; human model; immune function; immune reconstitution; improved; in vivo imaging; insight; lymph nodes; molecular imaging; mortality; mortality risk; new technology; nonhuman primate; pathogen; prevent; programs; pulmonary granuloma; radiological imaging; response; time interval; tool; tuberculosis drugs; tuberculosis treatment; virtual

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.

尽管全球医疗保健取得了重大进展，但估计有15万人死亡和1000万新的死亡人数 2018年的结核病病例（TB）。近100万HIV患者发生结核病（TB）。共同 HIV和TB感染与TB药物的高发病，死亡率以及治疗有关 逆转录病毒（ART）疗法现已普遍可用。结核病治疗随后是艺术品长期改善 生存期，特别是在免疫系统因HIV感染严重抑制的人中。标志 疾病的症状开始后很快得到改善，但在许多情况下，疾病会复发，并且 随着免疫系统从艺术中重新建立，临床上似乎更糟。这被称为tb- 相关的免疫重构炎症综合征（TB-IRI），在患者中更为常见 治疗前严重抑制了免疫系统，而在 开始结核病治疗和艺术。关于如何或为什么发生TB-iris以及如何最好地治疗的知之甚少 甚至阻止它。我们假设TB-IRI的症状是由动态相互作用驱动的 免疫系统，结核分枝杆菌（MTB，导致结核病的细菌）和HIV深处 体内感染的组织，例如肺肉芽肿。几乎没有什么了解 MTB和HIV在TB-IRIS期间相互作用的组织。该提案将开发出TB-的动物模型 虹膜通过利用我们先前存在的HIV-TB共感染模型，其中具有SIV-MTB共同的动物 感染像人类一样接受结核病药物治疗和艺术。我们将使用复杂的成像， 免疫学和微生物学工具可以更好地了解TB-IRIS如何以及为什么发展的原因以及哪些因素可以 预测其出现。 AIM 1将确定TB-IRI在此模型中发生的频率以及MTB和 在治疗过程中，SIV保留在组织中。我们还将对更改进行详细检查 发生在组织中，尤其是肺（肉芽肿）和淋巴结通过体内图像到 更好地了解导致TB-IRI及其预测因素的事件。在AIM 2中，我们将执行详细的 检查组织中的免疫事件和TB-IRIS期间的血液。组织特异性（肺 肉芽肿和淋巴结）免疫反应将与MTB细菌的量相关 随着成像发现，我们可以更好地理解TB-IRIS的原因。我们的短期目标是 更好地了解该提案中TB-IRI的发病机理，这些发现最终将导致更好 治疗和预防TB-IRI，这是我们的长期目标。