This project will identify antigen-specific human T cell signatures that allow progression to active TB disease, by prospectively collecting samples from high risk household TB contacts, and comparing M. tuberculosis antigen-specific T cell responses in those that subsequently progress to active TB and in those that do not. We will characterize the breadth (number of antigens) and specific patterns of antigen recognition by T cells, and we will determine the relationship between the subjects' T cell responses, their HLA allotypes, and their bacterial epitope sequences, to test two specific hypotheses: 1) that the ability of an individual's T cells to respond to M. tuberculosis epitopes is determined by the ability of that individual's HLA alleles to present the specific epitope sequences present in the bacteria that infected them; and 2) that the breadth and/or specific nature of antigen recognition is associated with the risk of progression to active TB. To provide more complete characterization of the molecular interactions between host and pathogen required for CD4 T cell responses, we will also characterize the diversity of T cell antigen receptors (TCRs) for selected epitopes, to test the hypothesis that subjects that progress to active TB have lower TCR diversity than do subjects that do not progress to active TB. In studies analogous to those in Project 1, we will use multiparameter mass cytometry to identify T cell phenotypes and/or functional responses characteristic of subsequent progression to active TB. The data from these studies will be used to synthesize T cell signatures associated with a lower or with a higher risk of progression to active TB; signatures associated with progression can be used to identify individuals at highest risk and prioritize them for preventive interventions, while low-risk signatures will guide TB vaccine development. We will also take advantage of our prospective study design to determine the extent to which latent TB infection (LTBI) protects against development of active TB after reexposure to an active TB case. Together, the proposed studies will provide unprecedented insight into the spectrum of antigen-specific T cell responses (T cell signatures) in humans infected with Mtb, and the association of specific T cell signatures with distinct outcomes.

Public Health Relevance

This project will define the differences in human immune responses that distinguish people that progress to active TB and those that do not progress. The information will be invaluable for identifying those at highest risk of progression, so that prevention efforts can be prioritized to them in order to prevent illness and TB transmission. In addition, the information gained from these studies will inform TB vaccine development, as it will distinguish effective and ineffective human immune responses to M tuberculosis antigens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI111211-03
Application #
9108856
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Emory University
Department
Type
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
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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
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:
Bolz, Miriam; Ernst, Joel D (2017) Fishing for Answers in Human Mycobacterial Infections. Immunity 47:395-397
Kapwata, Thandi; Morris, Natashia; Campbell, Angela et al. (2017) Spatial distribution of extensively drug-resistant tuberculosis (XDR TB) patients in KwaZulu-Natal, South Africa. PLoS One 12:e0181797

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