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

Abstract

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 theoreticalmore » 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.« less

Authors:
 [1];  [2];  [1]
  1. Univ. of Houston, TX (United States). Dept. of Biomedical Engineering
  2. Sandia National Lab. (SNL-NM), Albuquerque, NM (United States). Center for Computing Research
Publication Date:
Research Org.:
Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA)
Contributing Org.:
Univ. of Houston, TX (United States)
OSTI Identifier:
1271015
Alternate Identifier(s):
OSTI ID: 1261102
Report Number(s):
SAND2016-6830J
Journal ID: ISSN 2235-2988; 645291
Grant/Contract Number:  
AC04-94AL85000; FA8650-10- 2-6062; K25HL075105; MCB-1445470
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Frontiers in Cellular and Infection Microbiology
Additional Journal Information:
Journal Volume: 6; Journal Issue: 6; Journal ID: ISSN 2235-2988
Publisher:
Frontiers Research Foundation
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Mycobacterium tuberculosis; agent based model; systems biology; granuloma; multiscale modeling; host-pathogen interactions; dormancy; lung diseases; 60 APPLIED LIFE SCIENCES

Citation Formats

Sershen, Cheryl L., Plimpton, Steven J., and May, Elebeoba E. Oxygen Modulates the Effectiveness of Granuloma Mediated Host Response to Mycobacterium tuberculosis: A Multiscale Computational Biology Approach. United States: N. p., 2016. Web. doi:10.3389/fcimb.2016.00006.
Sershen, Cheryl L., Plimpton, Steven J., & May, Elebeoba E. Oxygen Modulates the Effectiveness of Granuloma Mediated Host Response to Mycobacterium tuberculosis: A Multiscale Computational Biology Approach. United States. https://doi.org/10.3389/fcimb.2016.00006
Sershen, Cheryl L., Plimpton, Steven J., and May, Elebeoba E. 2016. "Oxygen Modulates the Effectiveness of Granuloma Mediated Host Response to Mycobacterium tuberculosis: A Multiscale Computational Biology Approach". United States. https://doi.org/10.3389/fcimb.2016.00006. https://www.osti.gov/servlets/purl/1271015.
@article{osti_1271015,
title = {Oxygen Modulates the Effectiveness of Granuloma Mediated Host Response to Mycobacterium tuberculosis: A Multiscale Computational Biology Approach},
author = {Sershen, Cheryl L. and Plimpton, Steven J. and May, Elebeoba E.},
abstractNote = {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.},
doi = {10.3389/fcimb.2016.00006},
url = {https://www.osti.gov/biblio/1271015}, journal = {Frontiers in Cellular and Infection Microbiology},
issn = {2235-2988},
number = 6,
volume = 6,
place = {United States},
year = {Mon Feb 15 00:00:00 EST 2016},
month = {Mon Feb 15 00:00:00 EST 2016}
}

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Cited by: 25 works
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Works referenced in this record:

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Mycobacterium tuberculosis Senses Host-Derived Carbon Monoxide during Macrophage Infection
journal, May 2008


Mycobacterial granulomas: keys to a long-lasting host–pathogen relationship
journal, November 2004


Identifying control mechanisms of granuloma formation during M. tuberculosis infection using an agent-based model
journal, December 2004


A methodology for performing global uncertainty and sensitivity analysis in systems biology
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A hybrid multi-compartment model of granuloma formation and T cell priming in Tuberculosis
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M. tuberculosis persistence, latency, and drug tolerance
journal, January 2004


Mycobacterium tuberculosis gene expression during adaptation to stationary phase and low-oxygen dormancy
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Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing
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  • Sershen, Cheryl L.; Plimpton, Steven J.; May, Elebeoba E.
  • 2014 36th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC)
  • https://doi.org/10.1109/embc.2014.6943590

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Reverse Engineering of Oxygen Transport in the Lung: Adaptation to Changing Demands and Resources through Space-Filling Networks
journal, August 2010


Hypoxia Prolongs Monocyte/Macrophage Survival and Enhanced Glycolysis Is Associated with Their Maturation under Aerobic Conditions
journal, June 2009


Multiscale Computational Modeling Reveals a Critical Role for TNF-α Receptor 1 Dynamics in Tuberculosis Granuloma Formation
journal, February 2011


Works referencing / citing this record:

In Vitro Granuloma Models of Tuberculosis: Potential and Challenges
journal, March 2019


Cryptococcus neoformans resists to drastic conditions by switching to viable but non-culturable cell phenotype
journal, July 2019


A computational model tracks whole-lung Mycobacterium tuberculosis infection and predicts factors that inhibit dissemination
journal, May 2020


Cryptococcus neoformans resists to drastic conditions by switching to viable but non-culturable cell phenotype
posted_content, June 2019


Modelling the effects of environmental heterogeneity within the lung on the tuberculosis life-cycle
journal, December 2020


Submuscular gluteal abcess: An unusual presentation of rare sacral tuberculosis
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Timing malaria transmission with mosquito fluctuations
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Horizontal gene transfer of Chlamydia: Novel insights from tree reconciliation
journal, April 2018


Cryptococcus neoformans resists to drastic conditions by switching to viable but non-culturable cell phenotype
journal, July 2019