Oxygen Modulates the Effectiveness of Granuloma Mediated Host Response to Mycobacterium tuberculosis: A Multiscale Computational Biology Approach

Sershen, Cheryl L.; Plimpton, Steven J.; May, Elebeoba E.

doi:10.3389/fcimb.2016.00006

Title: Oxygen Modulates the Effectiveness of Granuloma Mediated Host Response to Mycobacterium tuberculosis: A Multiscale Computational Biology Approach

Journal Article · Mon Feb 15 04:00:00 UTC 2016 · Frontiers in Cellular and Infection Microbiology

DOI: https://doi.org/10.3389/fcimb.2016.00006 · OSTI ID:1261102

Sershen, Cheryl L. ^[1]; Plimpton, Steven J. ^[2]; May, Elebeoba E. ^[1]

Univ. of Houston, Houston, TX (United States)
Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

Mycobacterium tuberculosis associated granuloma formation can be viewed as a structural immune response that can contain and halt the spread of the pathogen. In several mammalian hosts, including non-human primates, Mtb granulomas are often hypoxic, although this has not been observed in wild type murine infection models. While a presumed consequence, the structural contribution of the granuloma to oxygen limitation and the concomitant impact on Mtb metabolic viability and persistence remains to be fully explored. We develop a multiscale computational model to test to what extent in vivo Mtb granulomas become hypoxic, and investigate the effects of hypoxia on host immune response efficacy and mycobacterial persistence. Our study integrates a physiological model of oxygen dynamics in the extracellular space of alveolar tissue, an agent-based model of cellular immune response, and a systems biology-based model of Mtb metabolic dynamics. Our theoretical studies suggest that the dynamics of granuloma organization mediates oxygen availability and illustrates the immunological contribution of this structural host response to infection outcome. Furthermore, our integrated model demonstrates the link between structural immune response and mechanistic drivers influencing Mtbs adaptation to its changing microenvironment and the qualitative infection outcome scenarios of clearance, containment, dissemination, and a newly observed theoretical outcome of transient containment. We observed hypoxic regions in the containment granuloma similar in size to granulomas found in mammalian in vivo models of Mtb infection. In the case of the containment outcome, our model uniquely demonstrates that immune response mediated hypoxic conditions help foster the shift down of bacteria through two stages of adaptation similar to thein vitro non-replicating persistence (NRP) observed in the Wayne model of Mtb dormancy. Lastly, the adaptation in part contributes to the ability of Mtb to remain dormant for years after initial infection.

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Research Organization:: Sandia National Laboratories (SNL-NM), Albuquerque, NM (United States)

Sponsoring Organization:: USDOE; National Nuclear Security Administration (NNSA)

Grant/Contract Number:: AC04-94AL85000

OSTI ID:: 1261102

Journal Information:: Frontiers in Cellular and Infection Microbiology, Journal Name: Frontiers in Cellular and Infection Microbiology Vol. 6; ISSN 2235-2988

Publisher:: Frontiers Research FoundationCopyright Statement

Country of Publication:: United States

Language:: English

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Reverse Engineering of Oxygen Transport in the Lung: Adaptation to Changing Demands and Resources through Space-Filling Networks Hou, Chen; Gheorghiu, Stefan; Huxley, Virginia H. PLoS Computational Biology, Vol. 6, Issue 8 https://doi.org/10.1371/journal.pcbi.1000902	journal	August 2010
A Novel In Vitro Multiple-Stress Dormancy Model for Mycobacterium tuberculosis Generates a Lipid-Loaded, Drug-Tolerant, Dormant Pathogen Deb, Chirajyoti; Lee, Chang-Muk; Dubey, Vinod S. PLoS ONE, Vol. 4, Issue 6 https://doi.org/10.1371/journal.pone.0006077	journal	June 2009
Multi-Scale Modeling Predicts a Balance of Tumor Necrosis Factor-α and Interleukin-10 Controls the Granuloma Environment during Mycobacterium tuberculosis Infection Cilfone, Nicholas A.; Perry, Cory R.; Kirschner, Denise E. PLoS ONE, Vol. 8, Issue 7 https://doi.org/10.1371/journal.pone.0068680	journal	July 2013
Mycobacterium tuberculosis WhiB3 Maintains Redox Homeostasis by Regulating Virulence Lipid Anabolism to Modulate Macrophage Response Singh, Amit; Crossman, David K.; Mai, Deborah PLoS Pathogens, Vol. 5, Issue 8 https://doi.org/10.1371/journal.ppat.1000545	journal	August 2009
Variability in Tuberculosis Granuloma T Cell Responses Exists, but a Balance of Pro- and Anti-inflammatory Cytokines Is Associated with Sterilization Gideon, Hannah Priyadarshini; Phuah, JiaYao; Myers, Amy J. PLOS Pathogens, Vol. 11, Issue 1 https://doi.org/10.1371/journal.ppat.1004603	journal	January 2015
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Hypoxia Prolongs Monocyte/Macrophage Survival and Enhanced Glycolysis Is Associated with Their Maturation under Aerobic Conditions Roiniotis, John; Dinh, Hang; Masendycz, Paul The Journal of Immunology, Vol. 182, Issue 12 https://doi.org/10.4049/jimmunol.0804216	journal	June 2009
Multiscale Computational Modeling Reveals a Critical Role for TNF-α Receptor 1 Dynamics in Tuberculosis Granuloma Formation Fallahi-Sichani, Mohammad; El-Kebir, Mohammed; Marino, Simeone The Journal of Immunology, Vol. 186, Issue 6 https://doi.org/10.4049/jimmunol.1003299	journal	February 2011
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Macrophage responses to hypoxia: relevance to disease mechanisms Lewis, J. S.; Lee, J. A.; Underwood, J. C. E. Journal of Leukocyte Biology, Vol. 66, Issue 6 https://doi.org/10.1002/jlb.66.6.889	journal	December 1999
Circuit-Based Models of Biomolecular System Dynamics May, Elebeoba E. Simulation and Verification of Electronic and Biological Systems https://doi.org/10.1007/978-94-007-0149-6_7	book	January 2011
Mathematical Model of Oxygen Transport in Tuberculosis Granulomas Datta, Meenal; Via, Laura E.; Chen, Wei Annals of Biomedical Engineering, Vol. 44, Issue 4 https://doi.org/10.1007/s10439-015-1415-3	journal	August 2015
Modeling Intercellular Interactions in Early Mycobacterium Infection Warrender, Christina; Forrest, Stephanie; Koster, Frederick Bulletin of Mathematical Biology, Vol. 68, Issue 8 https://doi.org/10.1007/s11538-006-9103-y	journal	May 2006
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Mycobacterial granulomas: keys to a long-lasting host–pathogen relationship Co, Dominic O.; Hogan, Laura H.; Kim, Shin-Il Clinical Immunology, Vol. 113, Issue 2 https://doi.org/10.1016/j.clim.2004.08.012	journal	November 2004
A systems chemical biology study of malate synthase and isocitrate lyase inhibition in Mycobacterium tuberculosis during active and NRP growth May, Elebeoba E.; Leitão, Andrei; Tropsha, Alexander Computational Biology and Chemistry, Vol. 47 https://doi.org/10.1016/j.compbiolchem.2013.07.002	journal	December 2013
Identifying control mechanisms of granuloma formation during M. tuberculosis infection using an agent-based model Segovia-Juarez, Jose L.; Ganguli, Suman; Kirschner, Denise Journal of Theoretical Biology, Vol. 231, Issue 3 https://doi.org/10.1016/j.jtbi.2004.06.031	journal	December 2004
A methodology for performing global uncertainty and sensitivity analysis in systems biology Marino, Simeone; Hogue, Ian B.; Ray, Christian J. Journal of Theoretical Biology, Vol. 254, Issue 1 https://doi.org/10.1016/j.jtbi.2008.04.011	journal	September 2008
A hybrid multi-compartment model of granuloma formation and T cell priming in Tuberculosis Marino, Simeone; El-Kebir, Mohammed; Kirschner, Denise Journal of Theoretical Biology, Vol. 280, Issue 1 https://doi.org/10.1016/j.jtbi.2011.03.022	journal	July 2011
M. tuberculosis persistence, latency, and drug tolerance Gomez, James E.; McKinney, John D. Tuberculosis, Vol. 84, Issue 1-2 https://doi.org/10.1016/j.tube.2003.08.003	journal	January 2004
Mycobacterium tuberculosis gene expression during adaptation to stationary phase and low-oxygen dormancy Voskuil, M. I.; Visconti, K. C.; Schoolnik, G. K. Tuberculosis, Vol. 84, Issue 3-4 https://doi.org/10.1016/j.tube.2004.02.003	journal	January 2004
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Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing Lin, Philana Ling; Ford, Christopher B.; Coleman, M. Teresa Nature Medicine, Vol. 20, Issue 1 https://doi.org/10.1038/nm.3412	journal	December 2013
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BioXyce: an engineering platform for the study of cellular systems Schiek, R. L.; May, E. E. IET Systems Biology, Vol. 3, Issue 2 https://doi.org/10.1049/iet-syb.2007.0086	journal	March 2009
Biochemical and Structural Studies of Malate Synthase from Mycobacterium tuberculosis Smith, Clare V.; Huang, Chih-chin; Miczak, Andras Journal of Biological Chemistry, Vol. 278, Issue 3 https://doi.org/10.1074/jbc.M209248200	journal	October 2002
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Tuberculous Granulomas Are Hypoxic in Guinea Pigs, Rabbits, and Nonhuman Primates Via, L. E.; Lin, P. L.; Ray, S. M. Infection and Immunity, Vol. 76, Issue 6 https://doi.org/10.1128/IAI.01515-07	journal	March 2008
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Growth of Virulent and AvirulentMycobacterium tuberculosis Strains in Human Macrophages Zhang, Ming; Gong, Jianhua; Lin, Yuanguang Infection and Immunity, Vol. 66, Issue 2 https://doi.org/10.1128/IAI.66.2.794-799.1998	journal	February 1998
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The Pulmonary Blood Volume in man* Dock, Donald S.; Kraus, William L.; McGuire, Lockhart B. Journal of Clinical Investigation, Vol. 40, Issue 2 https://doi.org/10.1172/jci104259	journal	February 1961
Kinetic modeling of tricarboxylic acid cycle and glyoxylate bypass in Mycobacterium tuberculosis, and its application to assessment of drug targets Singh, Vivek Kumar; Ghosh, Indira Theoretical Biology and Medical Modelling, Vol. 3, Issue 1 https://doi.org/10.1186/1742-4682-3-27	journal	August 2006
GSMN-TB: a web-based genome-scale network model of Mycobacterium tuberculosis metabolism Beste, Dany JV; Hooper, Tracy; Stewart, Graham Genome Biology, Vol. 8, Issue 5 https://doi.org/10.1186/gb-2007-8-5-r89	journal	January 2007
Differences in Reactivation of Tuberculosis Induced from Anti-TNF Treatments Are Based on Bioavailability in Granulomatous Tissue Marino, Simeone; Sud, Dhruv; Plessner, Hillarie PLoS Computational Biology, Vol. 3, Issue 10 https://doi.org/10.1371/journal.pcbi.0030194	journal	January 2007
Differences in reactivation of tuberculosis induced from anti-TNF treatments are based on bioavailability in granulomatous tissue Marino, Simeone; Sud, Dhruv; Plessner, Hillarie PLoS Computational Biology, Vol. preprint, Issue 2007 https://doi.org/10.1371/journal.pcbi.0030194.eor	journal	January 2005
Reverse Engineering of Oxygen Transport in the Lung: Adaptation to Changing Demands and Resources through Space-Filling Networks Hou, Chen; Gheorghiu, Stefan; Huxley, Virginia H. PLoS Computational Biology, Vol. 6, Issue 8 https://doi.org/10.1371/journal.pcbi.1000902	journal	August 2010
A Novel In Vitro Multiple-Stress Dormancy Model for Mycobacterium tuberculosis Generates a Lipid-Loaded, Drug-Tolerant, Dormant Pathogen Deb, Chirajyoti; Lee, Chang-Muk; Dubey, Vinod S. PLoS ONE, Vol. 4, Issue 6 https://doi.org/10.1371/journal.pone.0006077	journal	June 2009
Multi-Scale Modeling Predicts a Balance of Tumor Necrosis Factor-α and Interleukin-10 Controls the Granuloma Environment during Mycobacterium tuberculosis Infection Cilfone, Nicholas A.; Perry, Cory R.; Kirschner, Denise E. PLoS ONE, Vol. 8, Issue 7 https://doi.org/10.1371/journal.pone.0068680	journal	July 2013
Mycobacterium tuberculosis WhiB3 Maintains Redox Homeostasis by Regulating Virulence Lipid Anabolism to Modulate Macrophage Response Singh, Amit; Crossman, David K.; Mai, Deborah PLoS Pathogens, Vol. 5, Issue 8 https://doi.org/10.1371/journal.ppat.1000545	journal	August 2009
Variability in Tuberculosis Granuloma T Cell Responses Exists, but a Balance of Pro- and Anti-inflammatory Cytokines Is Associated with Sterilization Gideon, Hannah Priyadarshini; Phuah, JiaYao; Myers, Amy J. PLOS Pathogens, Vol. 11, Issue 1 https://doi.org/10.1371/journal.ppat.1004603	journal	January 2015
Physiological, ex vivo cell oxygenation is necessary for a true insight into cytokine biology Ivanovic, Zoran European Cytokine Network, Vol. 20, Issue 1 https://doi.org/10.1684/ecn.2009.0144	journal	March 2009
A systems chemical biology study of malate synthase and isocitrate lyase inhibition in Mycobacterium tuberculosis during active and NRP growth Alexander, Tropsha,; E., May, Elebeoba; I., Oprea, Tudor The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/3at9-jd55	text	January 2013
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Synergy between Individual TNF-Dependent Functions Determines Granuloma Performance for Controlling Mycobacterium tuberculosis Infection Ray, J. Christian J.; Flynn, JoAnne L.; Kirschner, Denise E. The Journal of Immunology, Vol. 182, Issue 6 https://doi.org/10.4049/jimmunol.0802297	journal	March 2009
Hypoxia Prolongs Monocyte/Macrophage Survival and Enhanced Glycolysis Is Associated with Their Maturation under Aerobic Conditions Roiniotis, John; Dinh, Hang; Masendycz, Paul The Journal of Immunology, Vol. 182, Issue 12 https://doi.org/10.4049/jimmunol.0804216	journal	June 2009
Multiscale Computational Modeling Reveals a Critical Role for TNF-α Receptor 1 Dynamics in Tuberculosis Granuloma Formation Fallahi-Sichani, Mohammad; El-Kebir, Mohammed; Marino, Simeone The Journal of Immunology, Vol. 186, Issue 6 https://doi.org/10.4049/jimmunol.1003299	journal	February 2011

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