Compounding effect of vitamin D3 diet, supplementation, and alcohol exposure on macrophage response to mycobacterium infection.

Vitamin D3 is known to be a key component in the defense against Mycobacterium tuberculosis (Mtb) infection through the regulation of cytokine and effector molecules. Conversely, alcohol exposure has been recognized as an immune dysregulator. Macrophages were extracted from D3 deficient and sufficient diet mice and supplemented with D3 or exposed to ethanol during ex vivo infection using M. bovis BCG, as a surrogate for Mtb. Results of our study indicate that while exogenous supplementation or alcohol exposure did alter immune response, in vivo diet was the greatest determinant of cytokine and effector molecule production. Alcohol exposure was found to profoundly dysregulate primary murine macrophages, with ethanol-exposed cells generally characterized as hyper- or hyporesponsive. Exogenous D3 supplementation had a normative effect for diet deficient host, however supplementation was not sufficient to compensate for the effects of diet deficiency. Vitamin D3 sufficient diet resulted in reduced cell cytotoxicity for the majority of time points. Results provide insight into the ramifications of both the individual and combined health risks of D3 deficiency or alcohol exposure. Given the clinical relevance of D3 deficiency and alcohol use comorbidities, outcomes of this study have implications in therapeutic approaches for the treatment of tuberculosis disease.

The dynamic immunomodulatory effects of vitamin D3 during Mycobacterium infection.

Mycobacterium tuberculosis ( Mtb), is a highly infectious airborne bacterium. Previous studies have found vitamin D3 to be a key factor in the defense against Mtb infection, through its regulation of the production of immune-related cytokines, chemokines and effector molecules. Mycobacterium smegmatis was used in our study as a surrogate of Mtb. We hypothesized that the continuous presence of vitamin D3, as well as the level of severity of infection would differentially modulate host cell immune response in comparison with control and the vehicle, ethanol. We found that vitamin D3 conditioning promotes increased bacterial clearance during low-level infection, intracellular containment during high-level infection, and minimizes host cytotoxicity. In the presence of vitamin D3 host cell production of cytokines and effector molecules was infection-level dependent, most notably IL-12, which increased during high-level infection and decreased during low-level infection, and NO, which had a rate of change positively correlated to IL-12. Our study provides evidence that vitamin D3 modulation is context-dependent and time-variant, as well as highly correlated to level of infection. This study furthers our mechanistic understanding of the dual role of vitamin D3 as a regulator of bactericidal molecules and protective agent against host cell damage.