Unraveling the role of fibrosis in the TB Granuloma

Abstract Tuberculosis (TB), a deadly infectious disease caused by the bacterium Mycobacterium tuberculosis (Mtb). The disease is characterized by the development of granulomas consisting of immune cells that form a cluster around the bacteria to limit bacterial growth and disease outcomes. Control of the TB epidemic is limited by a complicated drug regimen, development of antibiotic resistance, and the lack of an effective vaccine against infection and disease. Fibrosis is common in older granulomas, and has been associated with both positive and negative disease outcomes. Little is known about fibrosis in TB, partly due to the fact that fibroblasts are difficult to identify using traditional antibody-based techniques. To provide insight into the role that fibrosis plays at a single granuloma scale, we have developed a computational, agent-based model of granuloma formation in the lung following infection with Mtb. In previously published work we have identified the mechanisms driving fibrosis within a granuloma i.e. how the granuloma environment effects fibrosis. Using immunohistochemistry, we have characterized fibroblasts and early collagen deposition in TB granulomas. Here we have extended this work to look at how fibrosis affects the ability of a granuloma to control bacteria, focusing on the role of both fibroblasts. Predictions show that early fibrosis alters the structure of the granuloma with few long-term effects on bacterial control, however late fibrosis decreases the promotability of bacterial dissemination. This work has implications on treatment options for TB that typically cause early fibrosis to occur.