Computational and Empirical Studies Predict Mycobacterium tuberculosis-Specific T Cells as a Biomarker for Infection Outcome

Identifying biomarkers for tuberculosis (TB) is an ongoing challenge in developing immunological correlates of infection outcome and protection. Biomarker discovery is also necessary for aiding design and testing of new treatments and vaccines. To effectively predict biomarkers for infection progression in any disease, including TB, large amounts of experimental data are required to reach statistical power and make accurate predictions. We took a two-pronged approach using both experimental and computational modeling to address this problem. We first collected 200 blood samples over a 2- year period from 28 non-human primates (NHP) infected with a low dose of Mycobacterium tuberculosis. We identified T cells and the cytokines that they were producing (single and multiple) from each sample along with monkey status and infection progression data. Machine learning techniques were used to interrogate the experimental NHP datasets without identifying any potential TB biomarker. In parallel, we used our extensive novel NHP datasets to build and calibrate a multi-organ computational model that combines what is occurring at the site of infection (e.g., lung) at a single granuloma scale with blood level readouts that can be tracked in monkeys and humans. We then generated a large in silico repository of in silico granulomas coupled to lymph node and blood dynamics and developed an in silico tool to scale granuloma level results to a full host scale to identify what best predicts Mycobacterium tuberculosis (Mtb) infection outcomes. The analysis of in silico blood measures identifies Mtb-specific frequencies of effector T cell phenotypes at various time points post infection as promising indicators of infection outcome. We emphasize that pairing wetlab and computational approaches holds great promise to accelerate TB biomarker discovery.
Author Summary Tuberculosis (TB) is a disease that is caused by infection after inhaling the bacterium Mycobacterium tuberculosis. Not everyone infected with TB bacteria becomes sick. As a result, two TB-related conditions have been categorized: latent TB infection (not sick but still harboring the bacteria) and active TB disease. If not treated properly, active TB disease can be fatal. Almost 1.3 million die of TB worldwide each year, with ~8,6 million new infections in 2013. No effective vaccine is available to protect against TB and treatment of infection with multiple antibiotics is lengthy (6–9 months), with non-compliance being a major factor for the emergence of drug-resistant strains. A key step in developing effective vaccines and possibly shorter treatment regimens is the ability to identify biomarkers that correlate prognosis and progression to infection (similar to how cholesterol levels are a measure of heart health). In this study we show how pairing computer modeling, statistics and mathematics with datasets derived from non-human primate studies can accelerate biomarker discovery, and offer a new approach to identifying correlates of protection that will be useful in clinical practice, particularly in developing countries where TB is most prevalent.