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

C. L. Sershen, S. J. Plimpton, E. E. May, Frontiers in Cellular and Infection Microbiology, 6, doi:10.3389/fcimb.2016.00006 (2016).

Mycobacterium tuberculosis (Mtb) is the second most lethal pathogen after HIV 1. In response to the invading Mtb, the body can develop tightly packed layers of immune cell structures, often in the lungs, called granulomas. Infection associated granuloma formation can be viewed as a structural im- mune response that can contain and halt the spread of the pathogen. 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. In several mammalian hosts, including non-human primates, Mtb granulomas are believed to be hypoxic, although this has not been observed in murine infection models 2. We develop a multi-scale computa- tional model to test to what extent in vivo Mtb granulomas become hypoxic in humans, and investigate the effects of hypoxia on host immune response efficacy and mycobacterial persistence. Our study inte- grates a model of oxygen diffusion in the extracellular space of alveolar tissue, an agent-based model of cellular immune response, and a systems biology-based model of Mtb intracellular dynamics. We incor- porate the physiological dynamics and effects of oxygen availability in two ways: cellular consumption and consequential changes in extracellular levels of oxygen; Mtb respiration and metabolism associated growth while in the extracellular compartment as well as growth post phagocytosis. Our theoretical studies suggest that the dynamics of oxygen availability mediates granuloma organization 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 Mtb's adaptation to its changing microenvironment and the qualitative infection outcome scenarios: clearance, containment and dissemination. We observed hypoxic regions in the containment granuloma similar in size to granulomas found in mammalian models of Mtb infection. In the case of the containment outcome, our model uniquely demonstrated that immune response mediated hypoxic (low oxygen) conditions help foster the shift down of bacteria through the two stages of adaptation similar to the in vitro non-replicating persistence (NRP) stages observed in the Wayne model of Mtb dormancy. The adaptation in part helps explain the ability of the pathogen to remain dormant for years and decades after initial infection.

Return to Publications page