(continued from page 312)
ity of adjacent genes. “We wanted to find out what genes were next
to the vitamin D response elements,” White recalls.
Two of these response elements proved to be neighbors of genes
that make antimicrobial peptides, cathelicidin and beta-defensin 2,
the researchers reported in 2004. When the researchers administered 1,25-D to a variety of cells, production of beta-defensin 2
increased “modestly,” White told Science News. In contrast, he says,
the gene for making cathelicidin “went boom! Its induction was
very, very strong.”
Almost a year later, while hunting for triggers for cathelicidin
production, Gombart confirmed the McGill finding. His group
had been administering various natural signaling agents to white
blood cells, which the immune system sends out to vanquish germs.
In these cells, “nothing turned on the cathelicidin gene to any
degree except vitamin D. And it really turned that gene on—just
cranked it up,” Gombart says. “I was completely surprised.”
Independently, dermatologist Mona Ståhle of the Karolinska
Institute in Stockholm reached a similar conclusion when she realized that both vitamin D and several antimicrobials, including
cathelicidin, are produced in the skin. She says, “It just came to
me—an intuitive thought—that maybe the sun, through vitamin D
production, might help regulate the skin’s antimicrobial response.”
So, her team administered an ointment containing a drug mimic
of 1,25-D to the skin of four healthy people. The salve hit “the jackpot, right away,” Ståhle says. In the May 2005 Journal of Investigative Dermatology, her team reported that where the ointment had
been applied, cathelicidin-gene activity skyrocketed as much as
100-fold. The team also found evidence of a localized increase in
the concentration of cathelicidin.
TACKLING TB AND MORE Those studies, though suggestive,
didn’t reveal whether vitamin D directly reduced infection risk in
people. Together with Gallo, microbial immunologist Robert Modlin of UCLA and his colleagues moved closer to that goal: They evaluated the vitamin’s role in fending off the tuberculosis (TB) germ
Mycobacterium tuberculosis.
This group, working independently of Gombart’s team, had been
focusing on macrophages, a type of white blood cell deployed by
the immune system to gobble up and destroy germs. These defense
cells have features, called toll-like receptors, that identify biochemical patterns characteristic of invading microbes. If the receptors
sense an invader, they can trigger cathelicidin production.
Modlin’s team showed that before making that antibiotic, those
cells briefly boosted their production of vitamin D receptors and of
an enzyme that converts the vitamin D prehormone into 1,25-D.
However, the data suggested that significant concentrations of
1,25-D would develop only in the presence of the TB bacteria. This
indicated that the microbe, and perhaps other germs, must be present for the enzyme to maximize its production of 1,25-D, Modlin says.
His group then tested whether people’s blood concentrations of
the prehormone are high enough to drive the production of germ-killing concentrations of cathelicidin. Black people, because of the
sun-filtering effect of dark pigments in their skin, are far more
likely than whites to be vitamin D deficient (SN: 10/16/04, p. 248).
Furthermore, blacks tend to be more susceptible to TB than whites
and to develop a more severe illness when infected.
The team collected blood serum from white people and from
blacks. When the researchers added TB bacteria, macrophages in
the serum from black participants produced 63 percent less cathelicidin—and were less likely to kill the germs—than were
macrophages incubated in serum from whites.
The scientists then added vitamin D to the serum from blacks
until concentrations of the prehormone matched those in the
serum from whites. This boosted the macrophages’ cathelicidin production and rates of TB-microbe killing to those seen when such
cells were incubated in serum from whites. Modlin’s group reported
its findings in the March 24 Science.
The new data may explain the difference between blacks and
whites in TB susceptibility. Modlin says, “We showed that serum
from African American individuals did not support the production of the antibiotic by immune cells, until the serum received supplemental vitamin D.”
“We’re now planning to do a clinical trial and treat African Americans who are deficient with vitamin D to correct their serum levels [of the prehormone] and see if this will change their antimicrobial response,” Modlin says.
Gallo is also planning a new trial.
His group will compare the effectiveness of supplemental vitamin D in
elevating cathelicidin concentrations
when administered as oral supplements or as a skin treatment.
The team expects to see the biggest
benefit in skin wounds. However,
Gallo predicts that even healthy skin
will exhibit somewhat elevated antimicrobial concentrations, signaling an
improved resistance to infection.
Sun exposure—in moderation—
might also prove therapeutic, Ståhle’s
team suggested in the November
2005 Journal of Investigative Dermatology. The scientists showed that
in eight fair-skinned people, a single dose of ultraviolet-B radiation—just enough to evoke some skin reddening the next day—
activated the vitamin D receptor and the cathelicidin gene in the
exposed skin.
Ståhle is now beginning a trial of people with skin infections. A
drug analog of 1,25-D will be applied to see whether it speeds
wound healing.
“We can
imagine one
day treating
infections … by
giving safe and
simple
substances—
like a vitamin."
— MICHAEL ZASLOFF,
GEORGETOWN UNIVERSITY
FLU TOO? Many other findings also suggested to Cannell’s team
that flu vulnerability might be tempered by adequate vitamin D
intake. The researchers have marshaled data, gleaned from 120 or
so reports over the past 70 years, suggesting a link between vitamin D and resistance to infections.
For instance, the researchers point to studies showing that in winter, colds, flu, and other respiratory diseases are more common and
more likely to be deadly than they are in summer. During winter,
ultraviolet-light exposure tends to be low because people spend
more time indoors and the atmosphere filters out more of the sun’s
rays, especially at mid and high latitudes.
Cannell’s group cites a 1997 study showing that the rate of pneumonia in Ethiopian children with rickets, and therefore a likely vitamin D deficiency, was 13 times as high as in children without that
disease. The researchers also point to five studies since the 1930s
that have linked reduced risks of infectious disease to dietary supplementation with cod liver oil, a rich source of vitamin D.
Although the arguments in the paper by Cannell’s group “are
provocative,” White says, “I find them believable.”
So does Gallo. “There are many microbes out there that rarely-to-never cause disease in immunocompetent individuals. It’s not
because the microbes don’t choose to infect us,” he notes. “It’s
because the body’s immune defense against the microbes is sufficient to control their proliferation.”
It’s possible, he says, that a shortfall in vitamin D might seriously
compromise that defense.
Gombart’s group is developing rodents in which vitamin D modulates cathelicidin.
Until such lab animals are available, vitamin D’s impact—even
on flu risk—“should be explored in clinical trials,” Zasloff says,
because the treatment poses little risk to people.
Moreover, he argues, the payoff from any positive finding “would
be amazing. Imagine being able to block the spread of epidemic
flu with appropriate doses of this vitamin.” ■
