Findings help explain why populations with low levels of the active form of the vitamin are more at risk
By Ishani Ganguli | February 24, 2006
Vitamin D mediates a key antimicrobial response in humans against Mycobacterium tuberculosis (TB), according to a new study in Science. The findings may help explain why African-Americans, who tend to carry lower levels of vitamin D, are more susceptible to TB.
The authors "were able to provide the complete series of molecular events that explains why African-American populations have enhanced susceptibility to TB and have a much more aggressive disease course," said John White at McGill University in Montreal, who did not participate in the study.
As part of the innate immune system, microbial clues such as bacterial lipopeptides activate mammalian Toll-like receptors (TLR), which trigger an antimicrobial response in monocytes. In mice, this process is mediated by nitric oxide. However, the study authors, based at the University of California at Los Angeles, found in an earlier study that inhibiting NO had no effect on the human pathway.
To investigate, the team, led by Robert Modlin, stimulated TLR heterodimers in vitro and analyzed the resulting gene expression profiles. They found selective up-regulation in monocytes of the gene for vitamin D receptor (VDR), which has been associated with antimicrobial activity. Another up-regulated gene, Cyp27B1, encodes the enzyme that converts vitamin D to its active form, 1,25-dihydroxyvitamin D3 (1,25D3).
Adding 1,25D3 to monocytes led to the dose-dependent induction and expression of cathelicidin, an antimicrobial peptide that an earlier study connected to vitamin D regulation. In another experiment, the researchers found that cathelicidin kills M. tuberculosis in infected monocytes.
The researchers next examined how endogenous vitamin D fit into the puzzle. "The technical breakthrough that allowed us to put everything together," said Modlin, was substituting fetal calf serum -- the default in immunology research -- with human serum, which contains five-fold greater amounts of pro-vitamin D. In human serum, TLR induction led to cathelicidin activity - except when either VDR or the vitamin D activating enzyme were inhibited, demonstrating the importance of both proteins in the pathway.
These findings, the authors hypothesized, may help explain why African-Americans experience a higher incidence and severity of TB than other groups. African-Americans are also known to have decreased pro-vitamin D levels in their serum, because higher melanin levels make them less efficient at absorbing UV light to produce vitamin D. Dietary factors play a role as well, Modlin told The Scientist.
Indeed, the group found that TLR activation triggered much lower levels of cathelicidin induction in African-American serum samples than in Caucasian. However, adding vitamin D to samples from African-Americans restored cathelicidin mRNA levels, suggesting that vitamin D supplements could boost innate immunity against TB and help treat the disease in these populations.
"They have now made a bridge between the primary signal that arrives at TLR2 receptors and the downstream antimicrobial response," said McGill's White, who headed the previous study showing that vitamin D induces cathelicidin expression. "There's always been this idea that vitamin D and vitamin D signaling are important for protection from infection with TB, but there hasn't been a whole lot of proof," said Margherita Cantorna at Penn State University, who did not participate in the study.
The results corroborate decades of medical evidence that UV light - which allows human skin to synthesize vitamin D -- has curative effects on infection, a finding that earned Niels Ryberg Finsen the 1903 Nobel Prize for his work with UV light and skin tuberculosis.
The next step "is to classify people according to skin pigmentation type and look at the correlation of vitamin D levels, tuberculosis, and induction of the pathway," Modlin said. Previous research has shown that polymorphisms in the vitamin D receptor gene correlate with variations in susceptibility to TB, so it will be interesting to see how SNPs contribute to VDR function, he added.
Future research will also follow other downstream targets of the TLR triggered pathway. "The notion that cathelicidin may be at the tip of an iceberg is an exaggeration, but it may not be the only antimicrobial gene that is regulated by Vitamin D," said White, whose own work has pinpointed at least one other candidate.
Links within this article
P.T. Liu et al., "Toll-Like receptor triggering of a vitamin D-mediated human antimicrobial response," Science, February 23, 2006.
John H. White
S. Thoma-Uszynski et al., "Induction of direct antimicrobial activity through mammalian toll-like receptors," Science, February 23, 2001.
Robert L. Modlin
T.T. Wang et al., "Cutting Edge: 1,25-Dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression," Journal of Immunology, September 1, 2004.
I. Ganguli, "Gene implicated in human pigment variation," The Scientist, December 16, 2005.
L. Bornman et al., "Vitamin D receptor polymorphisms and susceptibility to tuberculosis in West Africa: a case-control and family study," Journal of Infectious Diseases, November 1, 2004.