Identifying immune correlates of control and protection to Mycobacterium tuberculosis (Mtb) infection is essential for designing vaccines for TB. The overall goals of our TBRU application are to identify antigen-specific T cell responses that are associated with distinct outcomes of Mtb infection: clearance, persistence, and progression to active disease. We currently lack the knowledge or tools to distinguish individuals who harbor persistent Mtb infection from those who may have resolved infection via immune-mediated clearance of bacteria. In Project 1 we will focus on """"""""Identification of human Mtb-specific T cell signatures that are associated with resolved and persistent Mtb infection"""""""". We will test the hypothesis that distinct Mtb-specific memory T cell profiles are associated with bacterial clearance or persistence. This is supported by our data showing that distinct antigen-specific memory T cell phenotypes and functions are associated with LTBI, active TB disease and clinically resolved TB. We propose to use chemotherapy-mediated clearance to model immune-mediated clearance of Mtb, as the treatment regimen for LTBI should result in significant reduction or elimination of bacteria. We will enroll individuals with LTBI in a low-exposure setting (Atlanta, GA) and systematically compare their antigen-specific T cell responses before and after treatment. We will delineate the spectrum of antigens recognized by Mtb-specific memory CD4 and CD8 T cells, characterize their memory phenotypes, functional capacities and transcriptional profiles (Aim 1). Using statistical analyses, we will derive Mtb-specific T cell signatures that represent bacterial clearance and persistence and evaluate these (with Project 3), in non-human primates (NHP) and determine the prevalence of these signatures in treatment-naive individuals with LTBI in Kenya (Aim 2). We will longitudinally assess the dynamics of Mtb-specific memory T cell responses and their homeostatic turnover in LTBI (Aim3). We will also compare clearance/persistence signatures with those associated with progression to TB (with Project 2). Overall, these studies will provide insights into protective immunity to TB and new tools to evaluate Mtb persistence or clearance in LTBI.

Public Health Relevance

Understanding the nature of human immune responses that are associated with the control or elimination of M. tuberculosis infection in humans is critical for developing vaccines that protect against tuberculosis and is the focus of this project.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-LG-M (M1))
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Emory University
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Ernst, Joel D (2018) Mechanisms of M. tuberculosis Immune Evasion as Challenges to TB Vaccine Design. Cell Host Microbe 24:34-42
Auld, Sara C; Shah, N Sarita; Mathema, Barun et al. (2018) Extensively drug-resistant tuberculosis in South Africa: genomic evidence supporting transmission in communities. Eur Respir J 52:
Whatney, Wendy E; Gandhi, Neel R; Lindestam Arlehamn, Cecilia S et al. (2018) A High Throughput Whole Blood Assay for Analysis of Multiple Antigen-Specific T Cell Responses in Human Mycobacterium tuberculosis Infection. J Immunol 200:3008-3019
Li, Kelin; Vorkas, Charles K; Chaudhry, Ashutosh et al. (2018) Synthesis, stabilization, and characterization of the MR1 ligand precursor 5-amino-6-D-ribitylaminouracil (5-A-RU). PLoS One 13:e0191837
Auld, Sara C; Shah, N Sarita; Cohen, Ted et al. (2018) Where is tuberculosis transmission happening? Insights from the literature, new tools to study transmission and implications for the elimination of tuberculosis. Respirology :
Nelson, Kristin N; Shah, N Sarita; Mathema, Barun et al. (2018) Spatial Patterns of Extensively Drug-Resistant Tuberculosis Transmission in KwaZulu-Natal, South Africa. J Infect Dis 218:1964-1973
Dhanda, Sandeep Kumar; Karosiene, Edita; Edwards, Lindy et al. (2018) Predicting HLA CD4 Immunogenicity in Human Populations. Front Immunol 9:1369
Scriba, Thomas J; Carpenter, Chelsea; Pro, Sebastian Carrasco et al. (2017) Differential Recognition of Mycobacterium tuberculosis-Specific Epitopes as a Function of Tuberculosis Disease History. Am J Respir Crit Care Med 196:772-781
Arlehamn, Cecilia S Lindestam; Copin, Richard; Leary, Shay et al. (2017) Sequence-based HLA-A, B, C, DP, DQ, and DR typing of 100 Luo infants from the Boro area of Nyanza Province, Kenya. Hum Immunol 78:325-326
Bablishvili, N; Tukvadze, N; Shashkina, E et al. (2017) Impact of gyrB and eis Mutations in Improving Detection of Second-Line-Drug Resistance among Mycobacterium tuberculosis Isolates from Georgia. Antimicrob Agents Chemother 61:

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