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Mathematical Model of Oxygen Transport in Tuberculosis Granulomas

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Abstract

Pulmonary granulomas—the hallmark of Mycobacterium tuberculosis (MTB) infection—are dense cellular lesions that often feature regions of hypoxia and necrosis, partially due to limited transport of oxygen. Low oxygen in granulomas can impair the host immune response, while MTB are able to adapt and persist in hypoxic environments. Here, we used a physiologically based mathematical model of oxygen diffusion and consumption to calculate oxygen profiles within the granuloma, assuming Michaelis–Menten kinetics. An approximate analytical solution—using a priori and newly estimated parameters from experimental data in a rabbit model of tuberculosis—was able to predict the size of hypoxic and necrotic regions in agreement with experimental results from the animal model. Such quantitative understanding of transport limitations can inform future tuberculosis therapeutic strategies that may include adjunct host-directed therapies that facilitate oxygen and drug delivery for more effective treatment.

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Acknowledgments

We thank Drs. Jerry Meldon and Stephen Matson for their insightful comments, and Drs. Vasileios Askoxylakis, Dai Fukumura, Giorgio Seano, Triantafyllos Stylianopoulos, and Joshua Tam for their assistance in manuscript editing. We would like to acknowledge Kathleen England, Daniel Schimel, and Danielle Weiner (Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, National Institutes of Health/National Institute of Allergy and Infectious Diseases) for their technical assistance in the previously performed animal studies. Thanks to Carolyn Smith (Edwin L. Steele Laboratories, Massachusetts General Hospital/Harvard Medical School) for her support in the immunohistochemistry studies. This study was supported in part by Grants from the Bill and Melinda Gates Foundation (to R.K.J.), through the Grand Challenges in Global Health Program to Douglas Young, Imperial College (to C.E.B.), and from the Intramural Research Program of the NIH, NIAID (to C.E.B).

Conflict of Interest

R.K.J. received consultant fees from Xtuit, Ophthotech, SPARC, and SynDevRx. R.K.J. owns equity in Enlight, Ophthotech, SynDevRx, and XTuit and serves on the Board of Directors of XTuit and the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund and Tekla World Healthcare Fund. No reagents or funding from these companies were used in these studies.

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Author notes

  1. Wei Chen

    Present address: Department of Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China

Authors and Affiliations

  1. Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Cox 7, 100 Blossom Street, Boston, MA, 02114, USA

    Meenal Datta, Wei Chen, Lei Xu & Rakesh K. Jain

  2. Department of Chemical and Biological Engineering, Tufts University, Medford, MA, 02155, USA

    Meenal Datta

  3. Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, 20892, USA

    Laura E. Via & Clifton E. Barry 3rd

  4. Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town, Rondebosch, Cape Town, 7701, South Africa

    Laura E. Via & Clifton E. Barry 3rd

  5. Departments of Biomedical and Mechanical Engineering, Bucknell University, Lewisburg, PA, 17837, USA

    James W. Baish

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  1. Meenal Datta
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Correspondence to Rakesh K. Jain.

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Associate Editor Aleksander S. Popel oversaw the review of this article.

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Datta, M., Via, L.E., Chen, W. et al. Mathematical Model of Oxygen Transport in Tuberculosis Granulomas. Ann Biomed Eng 44, 863–872 (2016). https://doi.org/10.1007/s10439-015-1415-3

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