The central theme of TBRU-ASTRa and its individual projects is to identify T cell signatures (the antigens recognized, the phenotypes, and the functions, of Mtb-specific T cells) associated with distinct states and outcomes of infection with Mtb.
Prevention of active TB in high burden regions would greatly benefit from a strategy to identify individuals with LTBI that are at highest risk for progression to active TB. However, despite the magnitude of the TB problem, it remains unclear why certain individuals cannot control infection with Mtb and progress to active TB, and others remain asymptomatic and healthy. Without this knowledge, it is not possible to identify those at highest risk of progression to active TB and prioritize them for preventive interventions.
The overall goal of TBRU-ASTRa is to contribute to the elimination of tuberculosis by generating a comprehensive understanding of antigen-specific T cell responses and their relationship to distinct outcomes of Mtb infection, including mycobacterial clearance, prolonged latent TB infection (LTBI), or progression from LTBI to active TB disease. The general hypotheses that TBRU-ASTRa will address are: 1) there are distinct states of Mtb infection that are currently considered to be a single category, LTBI; 2) that differences in antigen-specific T cell responses accompany distinct states of Mtb infection; 3) that these differences in antigen-specific T cell responses can be detected through analysis of peripheral blood T cells; and 4) that distinct antigen-specific T cell responses contribute to determining the outcome of infection with Mtb. To test these hypotheses, we have assembled an outstanding multidisciplinary group of investigators with expertise in immunology, clinical TB management and epidemiology, nonhuman primate TB, and clinical/translational research from Emory University, NYU School of Medicine, Tulane National Primate Research Center, the DeKalb County (Georgia) Board of Health, U.S. Centers for Disease Control (CDC), Kenya Medical Research Institute, La Jolla Institute of Allergy and Immunology, and Aeras. The overall TBRU-ASTRa Specific Aims include:
Specific Aim 1. Use state of the art concepts and technologies to define the spectrum of antigen recognition, T cell phenotypes, and T cell functions that develop in humans and in nonhuman primates infected with Mtb.
Specific Aim 2. In prospective studies, define explicit profiles of antigen specific T cell responses associated with distinct states of Mtb infection, including past but not present infection, stable LTBI, and LTBI that subsequently progresses to active TB.
Specific Aim 3. Develop tools to identify people at highest risk of progressing to active TB, so those people can be prioritized for preventive interventions.
Specific Aim 4. Identify antigen specific T cell responses associated with efficacious immunity to Mtb, to guide development of effective TB vaccines.
Specific Aim 5. Optimize a nonhuman primate model of TB for high-resolution studies of immunity to Mtb and the potential role of immunity in eradicating the bacteria.
Specific Aim 6. Define the impact of re-exposure and reinfection on antigen specific T cell responses and progression from LTBI to active TB.