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Synergy between Individual TNF-Dependent Functions Determines Granuloma Performance for Controlling Mycobacterium tuberculosis Infection¹

J. Christian J. Ray^2,*, JoAnne L. Flynn and Denise E. Kirschner^3,*

^* Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109; and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261

Mycobacterium tuberculosis is one of the world’s most deadly human pathogens; an integrated understanding of how it successfully survives in its host is crucial to developing new treatment strategies. One notable characteristic of infection with M. tuberculosis is the formation of granulomas, aggregates of immune cells whose structure and function may reflect success or failure of the host to contain infection. One central regulator of host responses to infection, including granuloma formation, is the pleiotropic cytokine TNF-. Experimental work has characterized roles for TNF in macrophage activation; regulation of apoptosis; chemokine and cytokine production; and regulation of cellular recruitment via transendothelial migration. Separating the effects of these functions is presently difficult or impossible in vivo. To this end, we applied a computational model to understand specific roles of TNF in control of tuberculosis in a single granuloma. In the model, cells are represented as discrete entities on a spatial grid responding to environmental stimuli by following programmed rules determined from published experimental studies. Simulated granulomas emerge as a result of these rules. After confirming the importance of TNF in this model, we assessed the effects of individual TNF functions. The model predicts that multiple TNF activities contribute to control of infection within the granuloma, with macrophage activation as a key effector mechanism for controlling bacterial growth. Results suggest that bacterial numbers are a strong contributing factor to granuloma structure with TNF. Finally, TNF-dependent apoptosis may reduce inflammation at the cost of impairing mycobacterial clearance.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants HL68526 (to D.E.K. and J.L.F.), NO1 AI50018 (to J.L.F. and D.E.K.), HL72682 (to D.E.K.), and LM00902701 (to D.E.K. and J.L.F.); the F.G. Novy Fellowship (to J.C.J.R.); and the Ellison Foundation (to J.L.F.).

² Current address: Department of Bioengineering, Rice University, Houston, TX 77251.

³ Address correspondence and reprint requests to Dr. Denise E. Kirschner, Department of Microbiology and Immunology, University of Michigan Medical School, 6730 Medical Science Building II, Ann Arbor, MI 48109-0620. E-mail address: kirschne{at}umich.edu

⁴ Abbreviations used in this paper: TB, tuberculosis; ABM, agent-based model; M_a, activated macrophage; M_ci, chronically infected macrophage; M_i, infected macrophage; M_r, resting macrophage; Mtb, Mycobacterium tuberculosis; T_move, probability of T cell movement onto an occupied location; s_TNF, overall rate of TNF production; T_reg, regulatory T cell.

⁵ The online version of this article contains supplemental material.

⁶ This result differs slightly from our previous results in Segovia-Juarez et al. (38 ), which predicted that intracellular growth rates are transiently negatively correlated with extracellular Mtb numbers between days 30 and 150 postinfection. This discrepancy is due to a peak in chronically infected macrophage bursting in that model, which is not reproduced in this study, because we hold the initial number of macrophages constant. This allows uncertainty analysis to have identical initial conditions between different parameter sets.