The bacterium that causes tuberculosis (TB), Mycobacterium tuberculosis (M.tb), has infected one third of the world's population. Infection occurs when the pathogen is inhaled, following exposure to a patient with lung TB. 10% of infected persons progress to disease, while 90% never do. We don't understand why some people develop disease, while others do not: this is the focus of this application. To address protection against TB, we have established a cohort of 6,363 South African adolescents. 53% were infected with M.tb at baseline. During 2 years of follow-up, 76 of these participants developed TB disease. As blood was collected and stored every 6 months, we have a unique opportunity to compare host responses between adolescents who developed disease and those who have remained healthy. We will have two approaches to defining protection. Our first focus will be on T cells, which are immune cells shown to be critical for protection against TB. Current assays focus on limited aspects of the T cell response, but have not been successful in defining protection. We have devised a new paradigm - we hypothesize that a model including multiple T cell functional attributes plus their regulation by multiple immune cells will define protection. We propose that relative """"""""immune quiescence"""""""", i.e., an optimal but relatively silent immune response, is associated with protection. We and others have preliminary data to suggest that too much inflammation, or too much activation of the immune system, may be detrimental. The rationale for our second focus is that our knowledge of host control of M.tb infection remains incomplete - we therefore propose an unbiased approach that will facilitate discovery of novel pathways involved in protection. We will assess genome-wide gene expression in blood cells, including purified immune cell populations, to delineate new pathways involved in protection. Our preliminary studies of protection against TB in infants have shown the incredible power of this approach. The longitudinal nature of the adolescent cohort, and state-of-the-art bioinformatic approaches, afford unique muscle for uncovering host determinants of protection. We will immediately validate findings by studying further groups of adolescents, from the same cohort. This will be followed by mechanistic studies aimed at understanding how newly described markers may act to protect us against TB. Knowledge of host determinants of protection against TB disease could impact TB control in many ways. For example, targeted prophylactic therapy for infected persons could be implemented, as well as rapid clinical testing of novel TB vaccines. Knowledge gained will also stimulate development of new vaccines and drugs against TB.

Public Health Relevance

Following exposure to the bacterium that causes tuberculosis, 10% of infected persons develop disease, while 90% never do. We will study differences in how these two groups of persons fight off the disease, to unravel new pathways involved in protection against TB. Knowledge gained may lead to targeted treatment of infected persons, to prevent disease, will allow rapid screening of new, better vaccines against tuberculosis, and will stimulate development of new vaccines and drugs against the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
4R01AI087915-03
Application #
8414796
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Jacobs, Gail G
Project Start
2010-12-15
Project End
2015-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
3
Fiscal Year
2013
Total Cost
$621,705
Indirect Cost
$46,052
Name
University of Cape Town
Department
Type
DUNS #
568227214
City
Rondebosch
State
Country
South Africa
Zip Code
7700
Suliman, Sara; Thompson, Ethan; Sutherland, Jayne et al. (2018) Four-gene Pan-African Blood Signature Predicts Progression to Tuberculosis. Am J Respir Crit Care Med :
Moguche, Albanus O; Musvosvi, Munyaradzi; Penn-Nicholson, Adam et al. (2017) Antigen Availability Shapes T Cell Differentiation and Function during Tuberculosis. Cell Host Microbe 21:695-706.e5
Suliman, Sara; Geldenhuys, Hennie; Johnson, John L et al. (2016) Bacillus Calmette-Guérin (BCG) Revaccination of Adults with Latent Mycobacterium tuberculosis Infection Induces Long-Lived BCG-Reactive NK Cell Responses. J Immunol 197:1100-1110
Fletcher, Helen A; Snowden, Margaret A; Landry, Bernard et al. (2016) T-cell activation is an immune correlate of risk in BCG vaccinated infants. Nat Commun 7:11290
Zak, Daniel E; Penn-Nicholson, Adam; Scriba, Thomas J et al. (2016) A blood RNA signature for tuberculosis disease risk: a prospective cohort study. Lancet 387:2312-2322
Kagina, Benjamin M; Mansoor, Nazma; Kpamegan, Eloi P et al. (2015) Qualification of a whole blood intracellular cytokine staining assay to measure mycobacteria-specific CD4 and CD8 T cell immunity by flow cytometry. J Immunol Methods 417:22-33
Nemes, Elisa; Kagina, Benjamin M N; Smit, Erica et al. (2015) Differential leukocyte counting and immunophenotyping in cryopreserved ex vivo whole blood. Cytometry A 87:157-65
Shey, Muki S; Nemes, Elisa; Whatney, Wendy et al. (2014) Maturation of innate responses to mycobacteria over the first nine months of life. J Immunol 192:4833-43
Soares, Andreia P; Kwong Chung, Cheong K C; Choice, Terry et al. (2013) Longitudinal changes in CD4(+) T-cell memory responses induced by BCG vaccination of newborns. J Infect Dis 207:1084-94
Kalsdorf, Barbara; Skolimowska, Keira H; Scriba, Thomas J et al. (2013) Relationship between chemokine receptor expression, chemokine levels and HIV-1 replication in the lungs of persons exposed to Mycobacterium tuberculosis. Eur J Immunol 43:540-9

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