Our TBRU focuses on immunity to M. tuberculosis (Mtb), to test the overall hypothesis that latent TB infection (LTBI) exists as a spectrum of bacterial and immunologic states, that at least three immunological states can be distinguished and correspond to: 1) past, but cleared Mtb infection; 2] stable LTBI with a low risk of progression to active disease; or 3) LTBI with a high risk of progression to active TB disease. To test this hypothesis, we will identify T cell signatures, consisting of the breadth of antigens recognized, the phenotypes, and the functions of Mtb-specific CD4 and CDB T cells, with correlations to outcomes determined in unique prospective studies in humans and in experimentally-infected nonhuman primates. In addition to unique prospective studies, we will use a novel 'Response Spectrum Assay' (RSA) that includes >60 strategically-selected Mtb antigens and epitope peptides, to assay the quantitative breadth and specific pattern of antigen recognition in LTBI subjects with distinct risks and rates of progreission to active TB. In addition, antigens and epitopes identified in the RSA will be used to design HLA-peptide tetramers for high-resolution studies of the phenotypes and functional capabilities of Mtb epitope-specific T cells. The results of these studies, which employ advanced technologies including mass cytometry (CyTOF), together with the results of the RSA, will be used to identify T cell signatures characteristic of distinct risk categories of LTBI. Certain of the validated T cell signatures will correspond to efficacious immune responses that are desirable targets of TB vaccine development, while others will be useful for identifying individuals with LTBI that are at highest risk of progression to active TB, so these individuals can be prioritized for preventive interventions. Our human studies will be conducted in Atlanta, GA, USA, and in collaboration with investigators at the Kenya Medical Research Institute/U.S. Centers for Disease Control (KEMRI/CDC); studies of TB in nonhuman primates will be done by experts at two national primate research centers (Yerkes and Tulane). The team we have assembled possesses a wide range of knowledge and expertise, and is poised to generate improved understanding of TB immunity to contribute to the elimination of TB.

Public Health Relevance

Although M. tuberculosis causes disease in only a fraction of infected people, the differences in immune responses in those that remain well or become sick are not well understood. We will apply cutting edge concepts and technologies in immunology to explain the different outcomes of Mtb infection. Our discoveries will provide tools to improve public health efforts, and will guide TB vaccine development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI111211-06
Application #
9754748
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Eichelberg, Katrin
Project Start
2014-08-11
Project End
2021-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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:

Showing the most recent 10 out of 15 publications