Experimental and Mathematical Approaches to Multi-Scale Analysis of Tumor Necrosis Factor-Regulated Immune Response to Tuberculosis

Tuberculosis (TB) is a common and deadly infectious disease caused by a highly successful bacterium, Mycobacterium tuberculosis (Mtb). Multiple host immune factors control the formation of a self-organizing aggregate of immune cells termed a granuloma in the lungs after inhalation of Mtb. One such factor, tumor necrosis factor-a (TNF), is a protein that regulates inflammatory immune responses. Availability of TNF within a TB granuloma has been proposed to have a critical role in protective immunity against TB. However, mechanisms at different time/length scales (e.g. molecular, cellular and tissue scales) that control TNF availability in a developing TB granuloma and their significance in determining the disease outcome (primary disease, latency, or TB reactivation) are poorly understood. To study the role of TNF and TNF receptors in the immune response to Mtb, we use an artificial experimental mouse model of TB. Granuloma formation in this model is induced in mice following injection of Sepharose beads covalently coupled to Mycobacterium purified protein derivative (PPD) antigen. PPD bead granulomas form at day 2 and reach their maximal size at day 4 following intravenous injection of PPD-coated beads. We investigate the role of TNF and the two known types of TNF receptors on the immune response to Mtb by performing experiments on normal mice as well as TNF or TNF receptor knockout mice and studying the size, morphology and cellular composition of granulomas measured using flow cytometry. Further, the mouse model is used to study the effects of mouse analogues of TNF-neutralizing drugs (that are used to treat inflammatory diseases and may cause TB reactivation) on size, morphology and cellular composition of granulomas to help explain why different drugs have been identified to induce distinct effects on TB reactivation. We also compare our experimental results with our first-generation multi-scale agent-based model that describes TNF-regulated immune response to TB. This model describes TNF-regulated immune responses to Mtb in the lung and includes a variety of mechanisms at both molecular and cellular scales. Taken together, our modeling and experimental data can help to elaborate relevant features of the immune response to Mtb infection, identifying new strategies for therapy/prevention.