Oxygen Modulates the Effectiveness of Granuloma Mediated Host Response to Mycobacterium tuberculosis: A Multiscale Computational Biology Approach
- Univ. of Houston, TX (United States). Dept. of Biomedical Engineering
- Sandia National Lab. (SNL-NM), Albuquerque, NM (United States). Center for Computing Research
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.
- Research Organization:
- Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)
- Sponsoring Organization:
- USDOE National Nuclear Security Administration (NNSA)
- Contributing Organization:
- Univ. of Houston, TX (United States)
- Grant/Contract Number:
- AC04-94AL85000; FA8650-10- 2-6062; K25HL075105; MCB-1445470
- OSTI ID:
- 1271015
- Alternate ID(s):
- OSTI ID: 1261102
- Report Number(s):
- SAND2016-6830J; 645291
- Journal Information:
- Frontiers in Cellular and Infection Microbiology, Vol. 6, Issue 6; ISSN 2235-2988
- Publisher:
- Frontiers Research FoundationCopyright Statement
- Country of Publication:
- United States
- Language:
- English
Web of Science
Similar Records
Emergence and selection of isoniazid and rifampin resistance in tuberculosis granulomas
Identifying mechanisms driving formation of granuloma-associated fibrosis during Mycobacterium tuberculosis infection