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

Warsinske, Hayley C.; DiFazio, Robert M.; Linderman, Jennifer J.; Flynn, JoAnne L.; Kirschner, Denise E.

doi:10.1016/j.jtbi.2017.06.017

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

Journal Article · Tue Jun 20 00:00:00 EDT 2017 · Journal of Theoretical Biology

DOI:https://doi.org/10.1016/j.jtbi.2017.06.017· OSTI ID:1463861

Warsinske, Hayley C. ^[1]; DiFazio, Robert M. ^[2]; Linderman, Jennifer J. ^[3]; Flynn, JoAnne L. ^[2]; Kirschner, Denise E. ^[1]

Univ. of Michigan Medical School, Ann Arbor, MI (United States). Dept. of Microbiology and Immunology
Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Dept. of Microbiology and Molecular Genetics
Univ. of Michigan, Ann Arbor, MI (United States). Dept. of Chemical Engineering

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.

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Research Organization:: Lawrence Berkeley National Laboratory, Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)

Sponsoring Organization:: USDOE Office of Science (SC), Advanced Scientific Computing Research (ASCR)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1463861

Alternate ID(s):: OSTI ID: 1576845

Journal Information:: Journal of Theoretical Biology, Vol. 429, Issue C; ISSN 0022-5193

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 28 works

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