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

项目总结 由结核分枝杆菌(Mtb)引起的结核病(TB)是导致人类死亡和死亡的主要原因。 5岁以下儿童死亡率。幼儿在初次感染后患结核病的易感性 这一关键的知识差距阻碍了开发更有效的疫苗和改进的努力 针对这一高危人群的诊断性测试。接触艾滋病毒(HEU)的儿童是生活在 HIV+成人的家庭，在那里他们比未接触HIV的未感染(HUU)儿童更有可能患结核病 暴露了。临床、流行病学和免疫学结果支持年轻的HEU儿童将表现出 结核分枝杆菌感染后的独特免疫反应；然而，对结核分枝杆菌感染的免疫反应没有 在这一高危人群中具有鲜明的特征。我们的提案将全面定义适应性免疫 儿童结核病家庭接触(HHC)研究对结核分枝杆菌暴露和儿童结核病的反应 在乌干达的坎帕拉，高达20%的儿童患有HEU。我们的方法将识别独特的免疫学 生物签名是由儿童在结核病病谱上所处的位置以及艾滋病毒暴露状态驱动的。我们 假设接触结核杆菌的无症状HEU儿童的免疫生物特征将更接近于 与无症状的HUU儿童相比，在结核病儿童中观察到的这些。如果得到证实，这将是 提示接触结核分枝杆菌的HEU儿童更有可能经历临床前而不是静止 或潜伏的结核分枝杆菌感染。这些发现将对基于免疫的诊断学的发展产生影响 对于结核分枝杆菌感染和结核病，在感染艾滋病毒和未接触艾滋病毒的儿童中表现也可能不同 作为结核病暴露后HEU儿童的临床管理和监测。使用生物储存库 从乌干达儿童5岁获得的样本，以及拟议的乌干达儿童5岁预期队列 我们将解决三个具体目标：1)定义纵向、功能性和表型结核分枝杆菌- 患结核病或无症状的幼儿中的特异性适应性免疫反应；2) 开发一组新的结核分枝杆菌表位和基于流式细胞术的检测结核分枝杆菌特异性的方法 幼儿的T细胞反应；以及3)建立独特的结核分枝杆菌特异性抗体Fc图谱，以定义儿童 得了肺结核。我们的建议将通过以下方式促进全球儿科健康：1)识别免疫学特征 反映成功控制了可作为保护性免疫相关的原发结核分枝杆菌感染 新的疫苗试验；2)开发新的基于血液的分析方法，区分患有 结核病和那些已经接触过但成功控制了感染的人。

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.