Cargando…

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

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 m...

Descripción completa

Detalles Bibliográficos
Autores principales: Sershen, Cheryl L., Plimpton, Steven J., May, Elebeoba E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753379/
https://www.ncbi.nlm.nih.gov/pubmed/26913242
http://dx.doi.org/10.3389/fcimb.2016.00006
_version_ 1782415851732860928
author Sershen, Cheryl L.
Plimpton, Steven J.
May, Elebeoba E.
author_facet Sershen, Cheryl L.
Plimpton, Steven J.
May, Elebeoba E.
author_sort Sershen, Cheryl L.
collection PubMed
description 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. The adaptation in part contributes to the ability of Mtb to remain dormant for years after initial infection.
format Online
Article
Text
id pubmed-4753379
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-47533792016-02-24 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. Front Cell Infect Microbiol Microbiology 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. The adaptation in part contributes to the ability of Mtb to remain dormant for years after initial infection. Frontiers Media S.A. 2016-02-15 /pmc/articles/PMC4753379/ /pubmed/26913242 http://dx.doi.org/10.3389/fcimb.2016.00006 Text en Copyright © 2016 Sershen, Plimpton and May. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
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
title Oxygen Modulates the Effectiveness of Granuloma Mediated Host Response to Mycobacterium tuberculosis: A Multiscale Computational Biology Approach
title_full Oxygen Modulates the Effectiveness of Granuloma Mediated Host Response to Mycobacterium tuberculosis: A Multiscale Computational Biology Approach
title_fullStr Oxygen Modulates the Effectiveness of Granuloma Mediated Host Response to Mycobacterium tuberculosis: A Multiscale Computational Biology Approach
title_full_unstemmed Oxygen Modulates the Effectiveness of Granuloma Mediated Host Response to Mycobacterium tuberculosis: A Multiscale Computational Biology Approach
title_short Oxygen Modulates the Effectiveness of Granuloma Mediated Host Response to Mycobacterium tuberculosis: A Multiscale Computational Biology Approach
title_sort oxygen modulates the effectiveness of granuloma mediated host response to mycobacterium tuberculosis: a multiscale computational biology approach
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753379/
https://www.ncbi.nlm.nih.gov/pubmed/26913242
http://dx.doi.org/10.3389/fcimb.2016.00006
work_keys_str_mv AT sershencheryll oxygenmodulatestheeffectivenessofgranulomamediatedhostresponsetomycobacteriumtuberculosisamultiscalecomputationalbiologyapproach
AT plimptonstevenj oxygenmodulatestheeffectivenessofgranulomamediatedhostresponsetomycobacteriumtuberculosisamultiscalecomputationalbiologyapproach
AT mayelebeobae oxygenmodulatestheeffectivenessofgranulomamediatedhostresponsetomycobacteriumtuberculosisamultiscalecomputationalbiologyapproach