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: 10667439
• 负责人: JoAnne L. Flynn
• 金额: $ 75.06万
• 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/10667439
• 关键词: Address; Adverse effects; Aftercare; Animal Model; Animals; Anti-Retroviral Agents; Antitubercular Agents; Autopsy; Bacteria; Biological; 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; Lung; Measures; Medical Research; Mission; Modality; Modeling; Molecular; Morbidity - disease rate; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Nature; PET/CT scan; Pathogenesis; Pathology; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Prednisone; Prevention; Prevention strategy; Process; Recurrence; 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; biological heterogeneity; biomarker identification; clinical predictors; co-infection; comparison control; global health; high risk; human disease; human model; immune function; immune reconstitution; improved; in vivo imaging; insight; lymph nodes; mortality; mortality risk; new technology; nonhuman primate; pathogen; prevent; programs; pulmonary granuloma; radiological imaging; response; synergism; 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，但估计仍有 150 万人死亡和 1000 万人新增死亡 2018 年结核病 (TB) 病例数。近 100 万艾滋病毒感染者罹患结核病 (TB)。共同 艾滋病毒和结核病感染与高发病率和死亡率以及结核病药物和抗结核药物治疗相关 逆转录病毒（ART）疗法现已普遍可用。结核病药物治疗后进行抗逆转录病毒治疗可长期改善 生存，特别是那些免疫系统因艾滋病毒感染而受到严重抑制的人。标志 开始治疗后疾病症状很快就会改善，但在许多情况下，疾病可能会复发，并且 随着免疫系统从 ART 中重建，临床症状似乎更糟。这被称为 TB- 相关的免疫重建炎症综合征 (TB-IRIS)，在患者中更为常见 治疗前免疫系统受到严重抑制以及治疗间隔时间短的患者 开始结核病治疗和抗逆转录病毒治疗。关于 TB-IRIS 如何或为何发生以及如何最好地治疗，人们知之甚少 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（Mtb，引起结核病的细菌）和体内深处的艾滋病毒 体内受感染的组织，例如肺肉芽肿。几乎不知道发生了什么 在 TB-IRIS 期间 Mtb 和 HIV 相互作用的组织。该提案将开发结核病动物模型 IRIS 通过利用我们预先存在的 HIV-TB 共感染模型，其中感染 SIV-Mtb 的动物 感染者像人类一样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 TB-IRIS 的形成方式和原因以及哪些因素可以 预测它的出现。目标 1 将确定该模型中 TB-IRIS 发生的频率以及 Mtb 和 Mtb 发生的程度。 SIV 在治疗期间保留在组织中。我们还将对这些变化进行详细检查 发生在组织中，尤其是肺（肉芽肿）和淋巴结中，通过连续的体内图像来 更好地了解导致 TB-IRIS 的事件及其预测因素。在目标 2 中，我们将执行详细的 检查 TB-IRIS 期间组织和血液中的免疫事件。组织特异性（肺 肉芽肿和淋巴结）免疫反应将与 Mtb 细菌和病毒的数量相关 结合影像学检查结果，以便我们更好地了解 TB-IRIS 的病因。我们的短期目标是 在本提案中更好地了解 TB-IRIS 的发病机制，这些发现最终将导致更好的结果 治疗和预防 TB-IRIS 是我们的长期目标。