Regulation of vitamin D metabolism during the immune response to mycobacterial infection
- Author(s): Zavala, Kathryn
- Advisor(s): Adams, John S;
- Hewison, Martin
- et al.
Classically, the endocrine vitamin D system is essential for maintaining calcium and phosphate homeostasis. Sufficient vitamin D levels promote bone health and prevent osteopathies, such as rickets and osteomalacia. However, the discovery of an intracrine vitamin D pathway alluded to other roles for vitamin D in regulating the immune system. Specifically, research on the innate immune response to Mycobacterium tuberculosis infection demonstrated a vitamin D-mediated antimicrobial response. Here, we continued to investigate the role of vitamin D in the immunobiology of mycobacterial infection. In Chapter 1, we studied mycobacterial infection using leprosy as a disease model. We demonstrated that induction of the type I IFN gene program during Mycobacterium leprae infection is an active immune evasion mechanism used to subvert the vitamin D-dependent antimicrobial response through the suppression of the vitamin D activating enzyme, CYP27B1. Moreover, our studies comparing macrophages associated with each of the two poles of the leprosy disease spectrum—lepromatous leprosy (L-lep) and tuberculoid leprosy (T-lep)—provided additional insight into susceptibility versus resistance to infection. T-lep-associated macrophages with elevated CYP27B1 expression and activity at baseline were resistant to type I IFN-mediated suppression and capable of inducing an antimicrobial response, whereas L-lep-associated macrophages were not. Taken together, these results demonstrate the importance of control of the vitamin D-dependent antimicrobial response in the host-pathogen interaction. In Chapter 2, we focused on markers of host defense to identify factors which confer protection against mycobacterial infection. These studies revealed that IL-32 is associated with IL-15- and IFN-γ-induced host defense networks. IL-32 is also necessary and sufficient to induce CYP27B1 activity and the downstream antimicrobial response. These studies pinpoint IL-32 as an important regulator of vitamin D-dependent host defense. Finally, in Chapter 3, we studied the effects of 1,25D on the iron regulatory protein, hepcidin, which regulates iron homeostasis by binding ferroportin and preventing the export of iron. Our results showed that 1,25D suppresses hepcidin expression in monocytes. These findings are important in the context of mycobacteria which are intracellular pathogens that rely on scavenging iron from the host to survive. Therefore, regulation of hepcidin may be another key battleground in the host-pathogen interaction.