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

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Book cover Systems Biology of Tuberculosis

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.

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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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Authors and Affiliations

  1. Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA

    Mohammad Fallahi-Sichani Ph.D.

  2. Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA

    Simeone Marino Ph.D. & Denise E. Kirschner Ph.D.

  3. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA

    JoAnne L. Flynn Ph.D.

  4. Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA

    Jennifer J. Linderman Ph.D.

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  1. Mohammad Fallahi-Sichani Ph.D.
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  2. Simeone Marino Ph.D.
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  3. JoAnne L. Flynn Ph.D.
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  4. Jennifer J. Linderman Ph.D.
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  5. Denise E. Kirschner Ph.D.
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Correspondence to Jennifer J. Linderman Ph.D. or Denise E. Kirschner Ph.D. .

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  1. Microbial and Cellular Sciences, University of Surrey, Guildford District, Guildford, GU2 5XH, Surrey, United Kingdom

    Johnjoe McFadden

  2. School of Biomedical and Molecular Scien, University of Surrey, Stag Hill, Guildford, GU2 7XH, Surrey, United Kingdom

    Dany J.V. Beste

  3. Faculty of Health and Medical Sciences, University of Surrey, Stag Hill, Guildford, GU2 5XH, Surrey, United Kingdom

    Andrzej M. Kierzek

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Fallahi-Sichani, M., Marino, S., Flynn, J.L., Linderman, J.J., Kirschner, D.E. (2013). A Systems Biology Approach for Understanding Granuloma Formation and Function in Tuberculosis. In: McFadden, J., Beste, D., Kierzek, A. (eds) Systems Biology of Tuberculosis. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4966-9_7

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