In Silico Model of Vitamin D3 Dependent NADPH Oxidase Complex Activation During Mycobacterium Infection

Mycobacterium tuberculosis (Mtb) is a highly infectious aerosolizable bacterium, which causes upward of 1.5 million deaths per year. Alveolar macrophages, the primary defense cell of the lung, are the preferred host cell of this intracellular bacterium. Vitamin D3 is a known transcription factor, modulating the transcription of pro- and anti-inflammatory cytokines and immunologically relevant proteins. In a vitamin D3 deficient host, the immune systems response to infection is greatly impaired. We used a quantitative systems biology approach to model the impact of long-term vitamin D3 deficiency on macrophage effector response. We then compared our simulation output to our in vitro model of mycobacterium infection of macrophages from vitamin D3 supplemented hosts. Our in silico model results agreed with in vitro levels of hydrogen peroxide (H2O2) production, an antimicrobial effector molecule produced by the host’s macrophage, known to be modulated indirectly by vitamin D3. The current model will provide a foundation for further studies into the effects of micronutrient deficiency on immune response.

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