A Systems Biology Approach for Understanding Granuloma Formation and Function in Tuberculosis

  • Mohammad Fallahi-Sichani
  • Simeone Marino
  • JoAnne L. Flynn
  • Jennifer J. Linderman
  • Denise E. Kirschner
Chapter

Abstract

The pathologic hallmark of tuberculosis is the granuloma. A granuloma is a multifaceted cellular structure that serves to focus the host immune response, contain infection and pathology, and provide a niche for the bacillus to persist within the host. Granulomas form in response to Mycobacterium tuberculosis infection, and if a granuloma is capable of inhibiting or killing most of the M. tuberculosis present, humans develop a clinically latent infection. However, if a granuloma is impaired in function, infection progresses, granulomas enlarge, and bacteria seed new granulomas; this results in progressive pathology and disease, i.e., active tuberculosis. In clinical latency, immunologic perturbation at the level of the granuloma can result in reactivation of infection. In humans, there are a variety of granuloma types, even within the lungs of a single host.

The roles and interactions of various cells (macrophages, T cells, B cells, and neutrophils) and molecules (cytokines, chemokines, and effector molecules) within a granuloma are complex and challenging to address by experimental methods alone. Computational approaches, in particular agent-based modeling, can be used to dissect the temporal and spatial aspects of granuloma formation and function. Here we explain how a systems biology approach can integrate experimental and computational work to address critical questions necessary to understanding granulomas and contribute to the development and testing of strategies for prevention and treatment.

Notes

Acknowledgements

This work was supported by National Institute of Health (NIH) grants R33 HL092844 (JJL), R33 HL092853 and R01 HL106804 (DEK), and JLF was supported by grants from the NIH (R01 HL71241, R33 HL092883, HL106804) and the Bill and Melinda Gates Foundation Grand Challenges and TB Drug Accelerator Programs. R01-EB-012579 was awarded to DEK, JLL, and JLF. MF was supported by a University of Michigan Rackham Predoctoral Fellowship. We also thank Mohammed El-Kebir and Paul Wolberg for helpful discussions. The authors declare that they have no competing financial interests.

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Copyright information

© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  • Mohammad Fallahi-Sichani
    • 1
  • Simeone Marino
    • 2
  • JoAnne L. Flynn
    • 3
  • Jennifer J. Linderman
    • 4
  • Denise E. Kirschner
    • 2
  1. 1.Department of Systems BiologyHarvard Medical SchoolBostonUSA
  2. 2.Department of Microbiology and ImmunologyUniversity of Michigan Medical SchoolAnn ArborUSA
  3. 3.Department of Microbiology and Molecular GeneticsUniversity of Pittsburgh School of MedicinePittsburghUSA
  4. 4.Department of Chemical EngineeringUniversity of MichiganAnn ArborUSA

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