A CD8+ T cell Diagnostic to Identify Children with Pulmonary Tuberculosis

描述（由申请人提供）：结核病（TB）是由结核分枝杆菌（Mtb）感染引起的疾病，是全世界5岁以下儿童感染性发病率和死亡率的主要原因。在结核病流行地区，全世界每年900万例结核病成人病例中的绝大多数居住在那里，5岁以下的儿童占总患者的30-40%，并且那些受感染的儿童往往患有更严重的、往往致命的结核病。5岁以下儿童结核病致死率的一个重要因素是该年龄组标准结核病诊断的表现不佳，特别是与成人相比。诊断不佳导致延误和漏诊，这反过来又导致儿童发病率和死亡率上升。目前，我们需要的是一种简单、强大的免疫诊断测试，可以区分儿童肺结核和非结核性肺炎。我们假设，针对Mtb肽的CD 8 + T细胞的检测可用于区分患有结核性肺炎的幼儿与患有非结核性肺炎的幼儿。在这方面，CD 8 + T细胞优先识别严重Mtb感染的细胞，我们在乌干达< 5岁的儿童中观察到，Mtb反应性CD 8 + T细胞在结核病儿童中检测到，而在无症状的Mtb感染/暴露儿童中未检测到。总之，这些数据表明，CD 8 + T细胞与细菌负荷相关。与此同时，我们已经通过我们的大规模抗原发现计划确定了45种免疫显性的、临床验证的CD 8 TB抗原，这些抗原被独家授权给ViTi，Inc.。从OHSU。为了开发一种改进的、广泛认可的诊断方法，我们计划使用生物信息学方法来定义这45种免疫显性CD 8抗原中可能含有免疫原性表位簇的肽。这些肽将被来自具有潜伏性TB感染（LTBI）的种族多样性成人或未感染成人的CD 8 + T细胞单独筛选以识别。在迭代过程中，我们将选择肽组以包含三个肽库;一个针对灵敏度优化，一个针对特异性优化，一个针对Mtb感染的灵敏度和特异性的平衡。对于未来的II期SBIR应用，这三种肽库将在一项比较乌干达和越南结核性肺炎儿童与非结核性肺炎儿童的CD 8 + T细胞应答的研究中作为儿童结核性肺炎的免疫诊断进行评估。 公共卫生相关性：结核病（TB）是全世界儿童传染病发病率和死亡率的最重要原因之一。幼儿更有可能从病原体结核分枝杆菌（Mtb）发展为严重的疾病。此外，儿童结核性肺炎很难诊断，导致延误和漏诊，进一步导致发病率和死亡率。这些研究的目的是开发一种简单，强大的免疫诊断测试，以区分幼儿结核性肺炎和非结核性肺炎。

DESCRIPTION (provided by applicant): Tuberculosis (TB) disease, which results from infection with Mycobacterium tuberculosis (Mtb), is a leading cause of infectious morbidity and mortality in children < 5 years old worldwide. In TB endemic regions, in which the vast majority of the world's annual 9 million adult cases of TB disease reside, children < 5 years old account for 30-40% of the total patients and those children who are infected tend to have more severe, often fatal forms of TB. A significant contributor to the deadliness of TB in children < 5 years old is the poor performance of standard TB diagnostics in this age group, especially as compared to adults. Poor diagnostics result in delayed and missed diagnoses, which in turn lead to increased morbidity and mortality in children. Currently, what is needed is a simple, robust immunodiagnostic test that will differentiate childhood pulmonary TB from non-TB pneumonia. We hypothesize that the detection of CD8+ T cells directed toward Mtb peptides can be utilized to distinguish young children with TB pneumonia from those with non-TB pneumonia. In this regard, CD8+ T cells preferentially recognize heavily Mtb-infected cells and we have observed in Ugandan children < 5 years old, that Mtb-reactive CD8+ T cells are detected in children with TB and not detected in asymptomatic children with Mtb infection/exposure. Taken together, these data suggest that CD8+ T cells correlate with bacterial burden. In parallel, we have defined 45 immunodominant, clinically- validated CD8 TB antigens through our large scale antigen discovery program that are exclusively licensed to ViTi, Inc. from OHSU. To develop an improved, broadly recognized diagnostic, we plan to use a bioinformatic approach to define peptides within these 45 immunodominant CD8 antigens likely to contain clusters of immunogenic epitopes. These peptides will be screened individually for recognition by CD8+ T cells from ethnically diverse adults with latent TB infection (LTBI) or uninfected adults. In an iterative process, we will select sets of peptides to comprise three peptide pools; one optimized for sensitivity, one for specificity, and one for a balance of sensitivity and specificity for Mtb infection. For a future Phase II SBIR application, these three peptide pools will be evaluated as an immunodiagnostic for TB pneumonia in children in a study comparing CD8+ T cell responses of Ugandan and Vietnamese children with TB pneumonia to those with non- TB pneumonia. PUBLIC HEALTH RELEVANCE: Tuberculosis (TB) is one of the most important causes of infectious morbidity and mortality in children worldwide. Young children are more likely to develop severe disease from the causative agent Mycobacterium tuberculosis (Mtb). Moreover, childhood TB pneumonia is difficult to diagnose resulting in delayed and missed diagnoses, further contributing to morbidity and mortality. The purpose of these studies is to develop a simple, robust immunodiagnostic test that distinguishes TB pneumonia from non-TB pneumonia in young children.