Multi-Scale Modeling Predicts a Balance of Tumor Necrosis Factor-a and Interleukin-10 Controls the Granuloma Environment during Mycobacterium tuberculosis Infection Nicholas A. Cilfone 1 , Cory R. Perry 2 , Denise E. Kirschner 2 *, Jennifer J. Linderman 1 * 1 Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, United States of America, 2 Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America Abstract Interleukin-10 (IL-10) and tumor necrosis factor-a (TNF-a) are key anti- and pro-inflammatory mediators elicited during the host immune response to Mycobacterium tuberculosis (Mtb). Understanding the opposing effects of these mediators is difficult due to the complexity of processes acting across different spatial (molecular, cellular, and tissue) and temporal (seconds to years) scales. We take an in silico approach and use multi-scale agent based modeling of the immune response to Mtb, including molecular scale details for both TNF-a and IL-10. Our model predicts that IL-10 is necessary to modulate macrophage activation levels and to prevent host-induced tissue damage in a granuloma, an aggregate of cells that forms in response to Mtb. We show that TNF-a and IL-10 parameters related to synthesis, signaling, and spatial distribution processes control concentrations of TNF-a and IL-10 in a granuloma and determine infection outcome in the long-term. We devise an overall measure of granuloma function based on three metrics – total bacterial load, macrophage activation levels, and apoptosis of resting macrophages – and use this metric to demonstrate a balance of TNF-a and IL-10 concentrations is essential to Mtb infection control, within a single granuloma, with minimal host-induced tissue damage. Our findings suggest that a balance of TNF-a and IL-10 defines a granuloma environment that may be beneficial for both host and pathogen, but perturbing the balance could be used as a novel therapeutic strategy to modulate infection outcomes. Citation: Cilfone NA, Perry CR, Kirschner DE, Linderman JJ (2013) Multi-Scale Modeling Predicts a Balance of Tumor Necrosis Factor-a and Interleukin-10 Controls the Granuloma Environment during Mycobacterium tuberculosis Infection. PLoS ONE 8(7): e68680. doi:10.1371/journal.pone.0068680 Editor: Deepak Kaushal, Tulane University, United States of America Received March 7, 2013; Accepted June 3, 2013; Published July 15, 2013 Copyright: ß 2013 Cilfone et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by National Institutes of Health (nih.gov) Grants R01 EB012579 and R01 HL110811 (JJL and DEK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: kirschne@umich.edu (DEK); linderma@umich.edu (JJL) Introduction Tuberculosis (TB) is an infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb). Approximately one-third of the world’s population is infected with Mtb, with 2–3 million deaths and an estimated 10 million new clinical cases each year [1,2]. Upon infection with Mtb, 5–10% of individuals develop active pulmonary TB, while about 90% develop a state of chronic infection, known as latent pulmonary TB, showing no clinical signs of disease [3–5]. Granulomas are structures which form in the lungs as a result of the immune response to inhaled Mtb. Granulomas serve as the central site of host-pathogen interaction during Mtb infection, with a host typically developing several granulomas based on the number of inhaled bacteria [4,6]. During latent pulmonary TB, granulomas are able to control Mtb but not completely eradicate the bacteria, while during active pulmonary TB Mtb growth is unrestrained in a portion of granulomas. The host factors that control the outcome of infection, in particular the formation and function of a granuloma, are not well understood and thus are difficult to use as therapeutic targets. Granulomas have a distinct cellular and spatial organization that creates a unique immune microenvironment in attempt to control infection. Bacteria and infected macrophages are found in the center of the structure and are surrounded by a region of mainly resting and activated macrophages (immune cells that phagocytose foreign material) followed by an outer cuff comprised predominantly of T cells (white blood cells that participate in cell- mediated immunity) [7–12]. Formation of a granuloma relies on coordinated immunological processes that include recruitment of immune cells to sites of infection, activation of macrophages, and production of particular molecular mediators known as cytokines [4,13–19]. Cytokines direct immune responses by influencing the fate and behavior of many immune cells. A pro-inflammatory cytokine, tumor necrosis factor-a (TNF-a), and an anti-inflamma- tory cytokine, interleukin-10 (IL-10), are hypothesized to be central to granuloma formation and function, but understanding the importance of each cytokine is complicated by the myriad of cellular and signaling processes acting across multiple spatial (tissue, cellular, molecular) and temporal (seconds to years) scales (Figure 1) [20–25]. PLOS ONE | www.plosone.org 1 July 2013 | Volume 8 | Issue 7 | e68680