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: 10591416
• 负责人: Christina Louise Lancioni
• 金额: $ 70.11万
• 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/10591416
• 关键词: Adult; Antibodies; B-Lymphocytes; Biological Assay; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Child; Childhood; Clinical; Clinical Management; Containment; Development; Diagnostic; Diagnostic tests; Disease; Epidemiology; Epitopes; Exhibits; Flow Cytometry; HIV; HIV Infections; 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; biobank; biosignature; cytokine; design; diagnostic tool; experience; global health; high risk; high risk population; improved; latent infection; mortality; novel; novel vaccines; pre-clinical; progression risk; reactivation from latency; response; 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.

项目摘要 由结核分枝杆菌（Mtb）引起的结核病（TB）是发病的主要原因， 5岁以下幼儿死亡率。幼儿在初次感染后易患结核病 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。 对这些高危人群进行诊断测试。受艾滋病毒感染的儿童占生活在农村地区的儿童的大多数。 艾滋病毒阳性成年人的家庭，他们比艾滋病毒未暴露未感染（HUU）的儿童更有可能患结核病 暴露了临床、流行病学和免疫学研究结果支持，高浓铀患儿会表现出 结核分枝杆菌暴露后独特的免疫反应;然而，对结核分枝杆菌感染的免疫反应没有 在这一高危人群中的特征。我们的建议将全面定义适应性免疫 使用儿科结核病家庭接触（HHC）研究， 在乌干达的坎帕拉，高达20%的儿童是高浓缩铀。我们的方法将确定独特的免疫学 由儿童在结核病谱上的位置以及艾滋病毒暴露状况驱动的生物特征。我们 假设暴露于结核分枝杆菌无症状高浓铀儿童的免疫生物特征更接近于 与无症状的HUU儿童相比，在结核病儿童中观察到的情况。如果得到证实， 表明Mtb暴露的高浓缩铀儿童更有可能经历临床前而不是静止期 或潜伏的结核杆菌感染。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可能在艾滋病毒暴露和未暴露的儿童中表现不同， 作为结核病暴露后高血糖儿童的临床管理和监测。与一个生物储存库合作， 从乌干达5岁以下儿童中获得的样本，以及拟议的乌干达5岁以下儿童前瞻性队列 谁是结核病HHC，我们将解决三个具体目标：1）定义纵向，功能和表型Mtb- 发生结核病或无症状的幼儿的特异性适应性免疫反应; 2） 开发新的Mtb表位库和定制的基于聚焦流式细胞术的检测Mtb特异性 幼儿中的T细胞应答;以及3）建立独特的Mtb特异性抗体Fc谱， 肺结核我们的提案将通过以下方式促进全球儿科健康：1）识别免疫学特征 反映了原发性Mtb感染的成功遏制，其可以作为保护性免疫的相关因素， 新的疫苗试验; 2）开发新的基于血液的检测方法， 结核病和那些已经暴露但成功控制感染的人。