Identifying control mechanisms of granuloma formation during M. tuberculosis infection using an agent-based model

Infection with Mycobacterium tuberculosis is a major world health problem. An estimated 2 billion people are presently infected and the disease causes approximately 3 million deaths per year. After bacteria are inhaled into the lung, a complex immune response is triggered leading to the formation of multicellular structures termed granulomas. It is believed that the collection of host granulomas either contain bacteria resulting in a latent infection or are unable to do so, leading to active disease. Thus, understanding granuloma formation and function is essential for improving both diagnosis and treatment of tuberculosis. Granuloma formation is a complex spatio-temporal system involving interactions of bacteria, specific immune cells, including macrophages, CD4+ and CD8+ T cells, as well as immune effectors such as chemokine and cytokines. To study this complex dynamical system we have developed an agent-based model of granuloma formation in the lung. This model combines continuous representations of chemokines with discrete agent representations of macrophages and T cells in a cellular automata-like environment. Our results indicate that key host elements involved in granuloma formation are chemokine diffusion, prevention of macrophage overcrowding within the granuloma, arrival time, location and number of T cells within the granuloma, and an overall host ability to activate macrophages. Interestingly, a key bacterial factor is its intracellular growth rate, whereby slow growth actually facilitates survival.