Understanding Variation in Macrophage Cell Death Following M. Tuberculosis Infection: A Systems Biology Approach

Abstract

Purpose: Macrophage apoptosis is considered an innate immune strategy of last resort in M. tuberculosis infection, while necrotic cell lysis is considered a feature of bacterial virulence. We built a mathematical model to investigate cell death decisions in mycobacterial infection, focusing on the role of the transcription factor NF-kB and the lipid mediators PGE2 and LXA4. The purpose of our model is to investigate proposed mechanisms, discern quantitative relationships among cell mediators, and to generate new testable hypotheses. Methods: We built a differential equation-based, mass-action kinetics model using PySB, an open-source software for biochemical modeling. We simulated our model using a personal computer. Results: We show how osmotic stress can account for experimental observations of necrosis due to mitochondrial dysfunction. We recapitulate the finding that PGE2 suppresses this dysfunction, and show how membrane repair pathways may prevent necrosis even for moderate degrees of mitochondrial injury. We show how a threshold level of LXA4-mediated PGE2 suppression is required to cause necrosis. Our simulations suggest that threshold LXA4 activity may also be required to induce apoptotic death. We also show how TNF and IL-10 shift the balance of cell death towards apoptosis and necrosis, respectively. Conclusions: To our knowledge, we are the first to formulate a mechanistic model for the events leading to necrotic cell lysis downstream of mitochondrial dysfunction. In addition to investigating the quantitative implications of existing hypotheses, our model also generates a novel hypothesis that the pro-necrotic mediator LXA4 may also be required for apoptosis, via attenuation of NFkB-mediated pro-survival pathways. This would represent an elegant mechanism for the selective application of apoptosis as an immune response. Future work should further elucidate the biochemical pathways linking bacterial virulence to LXA4 production and LXA4 to the suppression of PGE2.