Mycobacterium tuberculosis - immune system dynamics through agent-based modeling methodology: an important step in accelerating vaccine discovery

Tuberculosis (TB) has existed for millennia and remains a major global health problem. It causes ill-health in millions of people each year and in 2015 was one of the top 10 causes of death worldwide, ranking above HIV/AIDS as one of the leading causes of death from an infectious disease. TB is a contagious airborne disease caused by the bacillus Mycobacterium tuberculosis (MTB). It typically affects the lungs (pulmonary TB) but also affects other sites (extrapulmonary TB). Approximately 1/3 of the world’s population is affected by the disease but without any symptoms (known as latent TB infection (LTBI)), and approximately 10% of these people will likely develop active disease during their lifetime and become capable of transmitting the mycobacterium. TB can be treated through the selection of four standards (first-line) drugs. However, there is currently no effective vaccine in preventing TB disease in adults, either before or after exposure to TB infection. In biomedical, pharmaceutical, and toxicology research, the safety and efficacy of biomedical products are ultimately tested on humans via clinical trials after prior laboratory testing in vitro and/or in vivo on animals. The complete development chain of a new biomedical product and its introduction to the market is very long and expensive. Alternative methodologies to reduce animal and human testing are needed to address the safety and efficacy issues of human clinical trials, the ethical ones, and the imperfection of predictions issued from laboratory and animal studies when applied to humans. Computer modeling and simulation are currently used to a certain degree in pharmacokinetics, pharmacodynamics, or mechanistic simulations. A research and technological roadmap on in-silico trials that use individualized computer simulations in testing interventional strategies is currently available, showing both strong interest and potential benefit of expanding the computer modeling in drugs and other biomedical products research. Most of the work carried out during the Ph.D. project falls under the main objectives of the STriTuVaD project. In this Ph.D. thesis, it has been extended the Universal Immune System Simulator (UISS) to simulate the dynamics of tuberculosis and its interactions (physiological model), i.e., the behavior of the Mycobacterium within the host organism and its interactions with the immune system (active and latent form scenario) (disease model). In addition, the mechanisms of action of isoniazid and RUTI® vaccine were developed (treatment model).