Research Project
8233301
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.
