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A multi-scale and multi-system approach to understand granuloma formation in TB

Denise Kirschner, PI
Departments of:
Microbiology and Immunology,
and Program in Bioinformatics Faculty
Phone: (734) 647-7722
Fax: (734) 764-7723
E-mail: kirschne@umich.edu

Other PIs on this project:

Dr. Jennifer Linderman, PI, Dept of Chemical Engineering, University of Michigan
Dr. JoAnne Flynn, PI, Dept of Molecular Biology and Genetics, University of Pittsburgh
Dr. Steven Kunkel, PI, Graduate Program in Immunology, University of Michigan

Students and postdoctoral Fellows on this project:

Dr. Simeone Marino, PhD, Dept of Microbiology and Immunology, University of Michigan

Technical support:

Paul Wolberg, Dept of Microbiology and Immunology, University of Michigan
Joseph Waliga, Dept of Microbiology and Immunology, University of Michigan

Project Summary:

Tuberculosis is responsible for 2 million deaths per year. The interplay between host and bacterial factors leads to different disease outcomes (latency, primary tuberculosis, reactivation tuberculosis). A key outcome is the formation of a collection of immune cells termed the granuloma. This structure acts not only as an immune microenvironment and a barrier to dissemination but also as a niche for long-term bacterial survival. The long-term goal of this project is to identify factors that contribute to different outcomes of M. tuberculosis infection. We hypothesize that these different infection outcomes are reflected locally at the level of the granuloma and that granuloma structure is the result of the interplay of events at organ, tissue, cellular, and molecular scales over the time course of minutes to years. Several models of granuloma formation in tuberculosis will be integrated: pulmonary granulomas induced by M. tuberculosis antigen (PPD) coated beads in vivo, M. tuberculosis infection in mice and non-human primates, and multi-scale in silico models. Our studies will include multiple spatial and temporal scales to address the following aims. Aim 1: Determine how specific immune cells and effector molecules in the lung influence the formation of different granuloma structures. Aim 2: Determine the role of dendritic cell and T cell trafficking between lung granuloma and draining lymph nodes in influencing granuloma development. Aim 3: Identify the mechanisms that determine TNF availability for the purpose of understanding how granulomas form as well as how treatment with anti-TNF-therapies leads to TB reactivation. Our interdisciplinary team's approach for integrating data and in silico models over the relevant biological and temporal scales will allow us to predict and test hypotheses regarding key factors that influence granuloma formation and structure. These factors are likely central to determining different disease outcomes following M. tuberculosis infection and will provide a new tool for testing therapies and vaccines against M. tuberculosis.
Disclaimer: The reprints available here are provided for your personal use only and may not be used for any commercial purpose without prior written permissions from the paper's publisher and author. The violation is subject to the U.S. Copyright Act of 1976, Title 17 U.S.C.

1) Publications derived from this project:

J. Christian J. Ray, JoAnne L. Flynn, and Denise E. Kirschner A Synergy between Individual TNF-Dependent Functions Determines Granuloma Performance for Controlling Mycobacterium tuberculosis Infection. Journal of Immunology, 2009, 182: pp 3706-3717

Denise E. Kirschner and Jennifer J. Linderman Mathematical and computational approaches can complement experimental studies of host pathogen interactions. Cellular Microbiology (2009) 11(4), doi:10.1111/j.1462-5822.2 009.01281.x

Jennifer J. Linderman, Thomas Riggs, Manjusha Pande, Mark Miller, Simeone Marino, and Denise E. Kirschner Characterizing the Dynamics of CD4+ T Cell Priming within a Lymph Node. Journal of Immunology (2010) - in press

Fallahi-Sichani, M., M. Schaller, D. Kirschner, S. Kunkel, and J. Linderman Identification of key processes that control tumor necrosis factor availability in a tuberculosis granuloma. (in revision for PLoS Computational Biology, 2009)

Simeone Marino, Amy Myers, JoAnne L. Flynn, Denise E. Kirschner TNF and IL-10 are major factors in modulation of the phagocytic cell environment in lung and lymph node in tuberculosis: a next generation two compartmental model. (submitted to JTB) February 2010 to Journal of Theoretical Biology

2) Publications related to this project:

Jose L. Segovia-Juarez, Suman Ganguli, and Denise Kirschner, Identifying control mechanism of granuloma formation during M. tuberculosis infection using an agent based model, Journal of Theoretical Biology. 231, Issue 3, Pages 357-376 2004.

Stewart T. Chang, Jennifer J. Linderman, and Denise E. Kirschner A role for multiple mechanisms in the inhibition of MHC class II- mediated antigen presentation by Mycobacterium tuberculosis, Proceedings of the National Academy of Sciences, USA, pps. 4530-4535 March 22, 2005 vol. 102 no. 12, 2005

David Gammack, Jose L. Segovia-Juarez, Suman Ganguli, Simeone Marino, and Denise Kirschner, Understanding the Immune Response in Tuberculosis Using Different Mathematical Models and Biological Scales, SIAM Journal of Multiscale Modeling and Simulation, Vol. 3, No. 2, pp. 312-345, 2005

Denise E. Kirschner, Stewart T. Chang, Thomas W. Riggs, Nicolas Perry, Jennifer J. Linderman, Toward a multi scale model of antigen presentation in immunity , Immunological Reviews 2007 Vol. 216:,pp. 93-118; Edited by: J. Mata and J. Cohen

Denise Kirschner, The Multi-scale Immune Response to Pathogens: M. tuberculosis as an Example , In Silico Immunology, Springer US, pp. 289-311, 2007, DOI 10.1007/978-0-387-39241-7, edited by J. Timmis and D. Flower

Modeling Methods and Tools:

Ordinary Differential Equations (several non-linear types, all continuous, determistic approaches) and Agent-based Model (stochastic, discrete approach)
Software Development: Languages and Tools:

Framework / Sharing Environment:

Open source software used in the lab, not currently involved in development frameworks.

Available PROGRAMS from this project:

Sensitivity and Uncertainty Analysis Methods

Exectuable for 2-Dimensional granuloma simulator
IMAG and Mutliscale modeling Consortium Group Website:

Secured Collaboration Environment:

Limited-access shared collaboration resource (requires login).

Software Sharing Programs:

MATLAB codes and documentation for shareware analysis tools created by our group.

SBML format of Models:

To make our models "sharing-friendly", we have prepared SBML format for the models in the papers in the following link that are derived from this study:


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Phone/Fax: (734) 647-7723