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Title: Identifying mechanisms driving formation of granuloma-associated fibrosis during Mycobacterium tuberculosis infection

Abstract

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a pulmonary pathogen of major global concern. A key feature of Mtb infection in primates is the formation of granulomas, dense cellular structures surrounding infected lung tissue. These structures serve as the main site of host–pathogen interaction in TB, and thus to effectively treat TB we must clarify mechanisms of granuloma formation and their function in disease. Fibrotic granulomas are associated with both good and bad dis- ease outcomes. Fibrosis can serve to isolate infected tissue from healthy tissue, but it can also cause difficulty breathing as it leaves scars. Little is known about fibrosis in TB, and data from non-human primates is just beginning to clarify the picture. This work focuses on constructing a hybrid multi-scale model of fibrotic granuloma formation, in order to identify mechanisms driving development of fibrosis in Mtb infected lungs. We combine dynamics of molecular, cellular, and tissue scale models from previously published studies to characterize the formation of two common sub-types of fibrotic granulomas: peripherally fibrotic, with a cuff of collagen surrounding granulomas, and centrally fibrotic, with collagen throughout granulomas. Uncertainty and sensitivity analysis, along with large simulation sets, enable us to identify mechanismsmore » differentiating centrally versus peripherally fibrotic granulomas. Furthermore, these findings suggest that heterogeneous cytokine environments exist within granulomas and may be responsible for driving tissue scale morphologies. Using this model we are primed to better understand the complex structure of granulomas, a necessity for developing successful treatments for TB.« less

Authors:
 [1];  [2];  [3];  [2];  [1]
+ Show Author Affiliations
  1. Univ. of Michigan Medical School, Ann Arbor, MI (United States). Dept. of Microbiology and Immunology
  2. Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Dept. of Microbiology and Molecular Genetics
  3. Univ. of Michigan, Ann Arbor, MI (United States). Dept. of Chemical Engineering
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory, Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)
Sponsoring Org.:
USDOE Office of Science (SC), Advanced Scientific Computing Research (ASCR)
OSTI Identifier:
1463861
Alternate Identifier(s):
OSTI ID: 1576845
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Theoretical Biology
Additional Journal Information:
Journal Volume: 429; Journal Issue: C; Journal ID: ISSN 0022-5193
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Warsinske, Hayley C., DiFazio, Robert M., Linderman, Jennifer J., Flynn, JoAnne L., and Kirschner, Denise E. Identifying mechanisms driving formation of granuloma-associated fibrosis during Mycobacterium tuberculosis infection. United States: N. p., 2017. Web. doi:10.1016/j.jtbi.2017.06.017.
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Warsinske, Hayley C., DiFazio, Robert M., Linderman, Jennifer J., Flynn, JoAnne L., & Kirschner, Denise E. Identifying mechanisms driving formation of granuloma-associated fibrosis during Mycobacterium tuberculosis infection. United States. doi:https://doi.org/10.1016/j.jtbi.2017.06.017
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Warsinske, Hayley C., DiFazio, Robert M., Linderman, Jennifer J., Flynn, JoAnne L., and Kirschner, Denise E. Tue . "Identifying mechanisms driving formation of granuloma-associated fibrosis during Mycobacterium tuberculosis infection". United States. doi:https://doi.org/10.1016/j.jtbi.2017.06.017. https://www.osti.gov/servlets/purl/1463861.
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@article{osti_1463861,
title = {Identifying mechanisms driving formation of granuloma-associated fibrosis during Mycobacterium tuberculosis infection},
author = {Warsinske, Hayley C. and DiFazio, Robert M. and Linderman, Jennifer J. and Flynn, JoAnne L. and Kirschner, Denise E.},
abstractNote = {Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a pulmonary pathogen of major global concern. A key feature of Mtb infection in primates is the formation of granulomas, dense cellular structures surrounding infected lung tissue. These structures serve as the main site of host–pathogen interaction in TB, and thus to effectively treat TB we must clarify mechanisms of granuloma formation and their function in disease. Fibrotic granulomas are associated with both good and bad dis- ease outcomes. Fibrosis can serve to isolate infected tissue from healthy tissue, but it can also cause difficulty breathing as it leaves scars. Little is known about fibrosis in TB, and data from non-human primates is just beginning to clarify the picture. This work focuses on constructing a hybrid multi-scale model of fibrotic granuloma formation, in order to identify mechanisms driving development of fibrosis in Mtb infected lungs. We combine dynamics of molecular, cellular, and tissue scale models from previously published studies to characterize the formation of two common sub-types of fibrotic granulomas: peripherally fibrotic, with a cuff of collagen surrounding granulomas, and centrally fibrotic, with collagen throughout granulomas. Uncertainty and sensitivity analysis, along with large simulation sets, enable us to identify mechanisms differentiating centrally versus peripherally fibrotic granulomas. Furthermore, these findings suggest that heterogeneous cytokine environments exist within granulomas and may be responsible for driving tissue scale morphologies. Using this model we are primed to better understand the complex structure of granulomas, a necessity for developing successful treatments for TB.},
doi = {10.1016/j.jtbi.2017.06.017},
journal = {Journal of Theoretical Biology},
number = C,
volume = 429,
place = {United States},
year = {2017},
month = {6}
}
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Journal Article:
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Publisher's Version of Record
DOI:  https://doi.org/10.1016/j.jtbi.2017.06.017
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Works referencing / citing this record:

Granulomatous Inflammation in Tuberculosis and Sarcoidosis: Does the Lymphatic System Contribute to Disease?
journal, October 2019

  • Patterson, Karen C.; Queval, Christophe J.; Gutierrez, Maximiliano G.
  • BioEssays, Vol. 41, Issue 11
  • DOI: 10.1002/bies.201900086

Dynamic balance of pro- and anti-inflammatory signals controls disease and limits pathology
journal, August 2018

  • Cicchese, Joseph M.; Evans, Stephanie; Hult, Caitlin
  • Immunological Reviews, Vol. 285, Issue 1
  • DOI: 10.1111/imr.12671

Deletion of TGF-β1 Increases Bacterial Clearance by Cytotoxic T Cells in a Tuberculosis Granuloma Model
journal, December 2017

  • Warsinske, Hayley C.; Pienaar, Elsje; Linderman, Jennifer J.
  • Frontiers in Immunology, Vol. 8
  • DOI: 10.3389/fimmu.2017.01843

IL-10 Impairs Local Immune Response in Lung Granulomas and Lymph Nodes during Early Mycobacterium tuberculosis Infection
journal, December 2019

  • Wong, Eileen A.; Evans, Stephanie; Kraus, Carolyn R.
  • The Journal of Immunology, Vol. 204, Issue 3
  • DOI: 10.4049/jimmunol.1901211
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