Defining adaptive immune responses to Mtb-infection and TB disease among young children with and without HIV-exposure

定义接触或未接触 HIV 的幼儿对 Mtb 感染和结核病的适应性免疫反应

• 批准号: 10393701
• 负责人: Christina Louise Lancioni
• 金额: $ 67.46万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10393701
• 关键词: Address; Adult; Antibodies; B-Lymphocytes; Biological Assay; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Child; Childhood; Clinical; Clinical Management; Containment; Custom; Development; Diagnostic; Diagnostic tests; Disease; Epidemiology; Epitopes; Exhibits; Flow Cytometry; HIV; HIV Infections; HIV/TB; Health; Home; Household; Immune; Immune response; Immunity; Immunologics; Individual; Infant; Infection; Knowledge; Life; Monitor; Morbidity - disease rate; Mothers; Mycobacterium tuberculosis; Phenotype; Pneumonia; Primary Infection; Prospective cohort; Pulmonary Tuberculosis; Sampling; T cell response; Tuberculosis; Uganda; Vaccines; Work; adaptive immune response; base; biobank; biosignature; cytokine; design; diagnostic tool; experience; global health; high risk; high risk population; improved; latent infection; mortality; novel; novel vaccines; pre-clinical; reactivation from latency; response; tuberculosis treatment; vaccine trial

PROJECT SUMMARY Tuberculosis disease (TB), caused by Mycobacterium tuberculosis (Mtb) is a leading cause of morbidity and mortality in young children <5 yr old. The vulnerability of young children to develop TB following primary infection is not understood; this critical knowledge gap hampers efforts to develop a more effective vaccine and improved diagnostic tests for this high-risk population. HIV-exposed (HEU) children are the majority of children living in the homes of HIV+ adults, where they are more likely than HIV-unexposed-uninfected (HUU) children to be TB exposed. Clinical, epidemiologic, and immunologic findings support that young, HEU children will exhibit distinctive immune responses following Mtb-exposure; however, immune responses to Mtb-infection have not been characterized in this high-risk population. Our proposal will comprehensively define adaptive immune responses to Mtb-exposure and TB in children < 5yr using a pediatric TB household contact (HHC) study based in Kampala, Uganda, where up to 20% of children are HEU. Our approach will identify unique immunologic biosignatures driven by where the child sits on the TB disease spectrum, as well as by HIV-exposure status. We hypothesize that immune biosignatures of Mtb-exposed asymptomatic HEU children will more closely resemble those observed among children with TB, as compared to asymptomatic HUU children. If proven, this would suggest that Mtb-exposed HEU children are more likely to be experiencing a pre-clinical rather than quiescent or latent Mtb-infection. Such findings would have implications for the development of immune-based diagnostics for Mtb-infection and TB disease that may perform differently in HIV-exposed and unexposed children, as well as clinical management and monitoring of HEU-children following TB exposure. Working with a biorepository of samples obtained from Ugandan children < 5 yr, and a proposed prospective cohort of Ugandan children < 5 yr who are TB HHC, we will address three specific aims that: 1) define longitudinal, functional and phenotypic Mtb- specific adaptive immune responses among young children who developed TB or remained asymptomatic; 2) develop a pool of novel Mtb-epitopes and focused flow cytometry-based assay customized to detect Mtb-specific T cell responses in young children; and 3) establish a unique Mtb-specific antibody Fc profile that defines children with TB. Our proposal will advance pediatric global health by: 1) identification of immunologic signatures reflecting successful containment of primary Mtb infection that can serve as correlates of protective immunity for novel vaccine trials; 2) development of novel blood-based assays that discriminate between young children with TB and those whom have been exposed but successfully contained their infection.

项目概要 结核病 (TB) 由结核分枝杆菌 (Mtb) 引起，是发病率和死亡率的主要原因 5岁以下幼儿的死亡率。幼儿在初次感染后易患结核病 不被理解；这一关键的知识差距阻碍了开发更有效的疫苗和改进疫苗的努力 针对这一高危人群的诊断测试。感染艾滋病毒（HEU）的儿童是生活在该地区的大多数儿童。 HIV 阳性成年人的家中，他们比未暴露于 HIV 的未感染 (HUU) 儿童更有可能患上结核病 裸露。临床、流行病学和免疫学研究结果表明，HEU 儿童将表现出 接触 Mtb 后出现独特的免疫反应；然而，对 Mtb 感染的免疫反应尚未 已在这一高危人群中得到了表征。我们的提案将全面定义适应性免疫 使用基于儿童结核病家庭接触 (HHC) 研究的 5 岁以下儿童对 Mtb 暴露和结核病的反应 在乌干达坎帕拉，高达 20% 的儿童使用高浓铀。我们的方法将识别独特的免疫学 生物特征由儿童在结核病谱上的位置以及艾滋病毒暴露状况驱动。我们 假设接触 Mtb 的无症状 HEU 儿童的免疫生物特征将更接近 与无症状 HUU 儿童相比，在结核病儿童中观察到的结果。如果被证明的话，这将 表明接触 Mtb 的 HEU 儿童更有可能经历临床前而非静止期 或潜伏性结核分枝杆菌感染。这些发现将对基于免疫的诊断的发展产生影响 结核分枝杆菌感染和结核病在暴露于艾滋病毒和未暴露于艾滋病毒的儿童中的表现也可能不同 作为结核病暴露后 HEU 儿童的临床管理和监测。使用生物样本库 从乌干达 5 岁以下儿童获得的样本，以及拟议的乌干达 5 岁以下儿童前瞻性队列 对于 TB HHC，我们将解决三个具体目标：1) 定义纵向、功能和表型 Mtb- 患有结核病或无症状的幼儿的特异性适应性免疫反应； 2） 开发一系列新型 Mtb 表位和基于流式细胞术的定制检测方法，用于检测 Mtb 特异性 幼儿的 T 细胞反应； 3) 建立定义儿童的独特 Mtb 特异性抗体 Fc 图谱 患有结核病。我们的提案将通过以下方式促进儿科全球健康：1）免疫特征识别 反映了原发性结核分枝杆菌感染的成功遏制，可以作为保护性免疫的相关因素 新型疫苗试验； 2）开发新的基于血液的检测方法来区分患有以下疾病的幼儿 结核病以及那些接触过但成功控制感染的人。