Active tuberculosis (TB) is a major cause of human death and disease. It is also the most common fatal opportunistic infection in HIV/AIDS worldwide. The current neonatal BCG vaccine does not provide notable protection against adult pulmonary TB and none of the vaccine candidates show efficacy in board and/or reliable protection against either infection or disease. Past studies have identified specific immune responses associated with protection. But simply boosting these responses as employed in most vaccine strategies was not sufficient to provide protection. Recent experiments indicate that persistent mycobacteria are in an active state, and that latent infection is maintained though an active immune response. A better understanding of how latent TB is controlled by the immune system is essential for developing therapeutic hypothesis that could open new avenues for clinical intervention. Other than transcriptional analysis, most studies of Mtb responses consist of targeted assays and a focus on either children or adult populations that show high disease rates. To better understand how latent TB is controlled, we have created a unique and powerful study design. First, we will use recently developed technologies, including mass cytometry (CyTOF) and RNAseq for broad, unbiased and high-throughput analyses. We will apply these powerful new techniques to a material collected from patients between 13-16 years old. This age group stratifies children and adults and is noted to be the ?golden age? in TB where mortality and mobility is low. With this adolescent cohort, we hope to reduce the complexity inherent to latency, which can vary from something close to sterilizing immunity to subclinical active disease. In addition, we will employ bioinformatics tools to integrate and infer across two the cellular and transcriptome profiling proposed in Aim 1 and 2. Furthermore, we will use a novel integrated computationally analyses to compare our results with other TB studies from public database in Aim 3. Our goal is to gain new insight into how the course of Mtb infection is controlled in adolescents as compared with that from adults and children, and to identify factors that mediate and/or predict transitions from latent infection to active disease.

Public Health Relevance

Active tuberculosis (TB) is a major cause of human death and disease. Despite intense effort, factors that influence disease outcome remain ill defined. We propose to use recent technology for unbiased and broad analyses of the human immune response, and couple it with multi-cohort meta-analyses of publicly available data sets, for unbiased and multi-dimensional analyses of immune response in latent Mtb infection to gain insights into protection against natural infection in latency and to identify features denoting transition from latent TB to active disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Eichelberg, Katrin
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Stanford University
Schools of Medicine
United States
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Roy Chowdhury, Roshni; Vallania, Francesco; Yang, Qianting et al. (2018) A multi-cohort study of the immune factors associated with M. tuberculosis infection outcomes. Nature 560:644-648