The Vitamin D–antimicrobial Peptide Pathway and Its Role in Protection against Infection

Adrian F Gombart

Disclosures

Future Microbiol. 2009;4(9):1151-1165. 

In This Article

Regulation of CAMP Gene Expression by Vitamin D is a Primate-specific Adaptation

We demonstrated that regulation of the CAMP gene by VDR and its ligand 1,25(OH)2vitamin D3 is not evolutionarily conserved in mice, rats or dogs because the promoters of their CAMP genes lack a VDRE.[38] The VDRE was found to be present in an AluSx short interspersed element present in the CAMP promoter of both chimps and humans, suggesting that this immune response is a primate-specific adaptation.[38] Recently, we provided evidence for the evolutionary conservation of this regulation in humans, apes, Old World monkeys and New World monkeys, but not prosimians.[88] This demonstrates that exaptation or co-option of vitamin D-mediated gene regulation by an AluSx short interspersed element provided a novel, biologically important innate immune response that is conserved in humans and nonhuman primates, but not other mammalian species. It is a convincing example of an evolutionarily-fixed, Alu-mediated divergence in steroid hormone nuclear receptor gene regulation between humans/primates and other mammals. This evolutionary conservation provides strong evidence that the TLR2/1–vitamin D–cathelicidin pathway evolved as a biologically important immune response mechanism for protecting human and nonhuman primates against infection.[88]

What is the selective advantage of placing the primate CAMP gene under the regulation of the vitamin D pathway? The human CAMP gene is not induced consistently by pro-inflammatory stimuli.[38,89–93] Additionally, infection of human macrophages with M. tuberculosis and other cell types with pathogens leads to the repression of the CAMP gene, whereas the murine CAMP gene is induced.[37,94,95] Acquisition of the VDRE by ancestral primates that likely possessed high levels of vitamin D, similar to today's nonhuman primates,[96] would have provided a pathway for induction of the CAMP gene in cells such as macrophages or epithelial barrier cells that are capable of activating the vitamin D pathway in response to infection or wounding.[25,43] The activation of the vitamin D pathway provides a way for human macrophages to prevent the suppression of the CAMP gene when activated with TLR2 or TLR4 ligands.[97] Thus, induction of the CAMP gene by 1,25(OH)2D3provides a possible mechanism for primates to counteract pathogen-mediated suppression and modulate the immune response.

The mouse model is a powerful tool for understanding biological processes. The lack of vitamin D regulation of the cathelicidin gene makes it a poor model to study this mechanism. Our group is developing a 'humanized' mouse that carries a portion of the human CAMP gene locus that allows for proper levels of CAMP expression in the appropriate tissues. In addition, the mouse will lack the murine CAMP gene.[63] This mouse model will provide opportunities to study the importance of the vitamin D–cathelicidin pathway in infectious disease models while leveraging the power of crossing into other murine transgenics or knockouts.

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