A Systems Biology Approach for Understanding Granuloma Formation and Function in Tuberculosis

Abstract The pathologic hallmark of tuberculosis is the granuloma. A granuloma is a multifaceted cellular structure that serves to focus the host immune response, contain infection and pathology, and provide a niche for the bacillus to persist within the host. Granulomas form in response to Mycobacterium tuberculosis infection, and if a granuloma is capable of inhibiting or killing most of the M. tuberculosis present, humans develop a clinically latent infection. However, if a granuloma is impaired in function, infection progresses, granulomas enlarge, and bacteria seed new granulomas; this results in progressive pathology and disease, i.e., active tuberculosis. In clinical latency, immunologic perturbation at the level of the granuloma can result in reactivation of infection. In humans, there are a variety of granuloma types, even within the lungs of a single host. The roles and interactions of various cells (macrophages, T cells, B cells, and neutrophils) and molecules (cytokines, chemokines, and effector molecules) within a granuloma are complex and challenging to address by experimental methods alone. Computational approaches, in particular agent-based modeling, can be used