Hi Folks - a while back I mentioned this article, about Vitamin D possibly
protecting against the common cold (and being generally good at helping us
ward off infection). Someone wrote back that I posted the wrong URL for the
article, so I'm attaching the whole thing here. Hope you find it
interesting, as I did.
Best,
Richard R
==========
The Antibiotic Vitamin
Deficiency in vitamin D may predispose people to infection
Janet Raloff
In April 2005, a virulent strain of influenza hit a maximum-security
forensic psychiatric hospital for men that's midway between San Francisco
and Los Angeles. John J. Cannell, a psychiatrist there, observed with
increasing curiosity as one infected ward after another was quarantined to
limit the outbreak. Although 10 percent of the facility's 1,200 patients
ultimately developed the flu's fever and debilitating muscle aches, none did
in the ward that he supervised.
WINTER WOES. Cold-weather wear and the sun's angle in the winter sky limit
how much ultraviolet light reaches the skin. This can add up to a deficiency
in production of vitamin D, which might explain why respiratory infections
are common and severe in winter.
"First, the ward below mine was quarantined, then the wards on my right,
left, and across the hall," Cannell recalls. However, although the 32 men on
his ward at Atascadero (Calif.) State Hospital had mingled with patients
from infected wards before their quarantine, none developed the illness.
Cannell's ward was the only heavily exposed ward left unaffected. Was it by
mere chance, Cannell wondered, that his patients dodged the sickness?
A few months later, Cannell ran across a possible answer in the scientific
literature. In the July 2005 FASEB Journal, Adrian F. Gombart of the
University of California, Los Angeles (UCLA) and his colleagues reported
that vitamin D boosts production in white blood cells of one of the
antimicrobial compounds that defends the body against germs.
Immediately, Cannell says, the proverbial lightbulb went on in his head:
Maybe the high doses of vitamin D that he had been prescribing to virtually
all the men on his ward had boosted their natural arsenal of the
antimicrobial, called cathelicidin, and protected them from flu. Cannell had
been administering the vitamin D because his patients, like many other
people in the industrial world, had shown a deficiency.
The FASEB Journal article also triggered Cannell's recollection that
children with rickets, a hallmark of vitamin D deficiency, tend to
experience more infections than do kids without the bone disease. He shared
his flu data with some well-known vitamin D researchers, and they urged him
to investigate further.
On the basis of more than 100 articles that he collected, Cannell and seven
other researchers now propose that vitamin D deficiency may underlie a
vulnerability to infections by the microbes that cathelicidin targets. These
include bacteria, viruses, and fungi, the group notes in a report available
online <http://dx.doi.org/10.1017/S0950268806007175
Epidemiology and Infection.
This is only a hypothesis, "but a very credible one" that deserves testing,
says immunologist Michael Zasloff of Georgetown University in Washington,
D.C.
Behind the hypothesis are recent studies that link vitamin D intake to
revved-up cathelicidin production. These investigations point to an
infection-fighting role for vitamin D, which is produced in skin exposed to
sunlight but is present in few foods.
A study published earlier this year that investigated the relationship
between vitamin D and susceptibility to tuberculosis also bolsters the idea
proposed by Cannell's team. Scientists have already planned a handful of
clinical trials to evaluate the antimicrobial benefits of vitamin D
supplementation.
Zasloff argues that if studies support the hypothesis, "we can imagine one
day treating infections not by giving somebody a drug, but by giving them
safe and simple substanceslike a vitamin."
Innate protection
Legions of germs come into contact with our bodies every day. Each microbe
seeks a host in which it can multiply. Most would-be invaders, however,
don't succeed; if not barred entry outright, they're destroyed by cellular
recruits called up to participate in local immune militias.
Scientists hadn't been sure what serves as the call to arms for these immune
cells and what triggers the production of their antibiotic arsenal, which
includes several chemical weapons.
Over the past 5 years, a spate of studies began to shed light on the rollout
of one of those munitionscathelicidin. Dermatologist and immunologist
Richard L. Gallo of the University of California, San Diego, a coauthor of
many of these studies, explains that cathelicidin "targets the bad guys." It
kills invaders by punching holes in the external membrane of a microbe,
permitting its innards to leak out.
Molecular geneticist John H. White of McGill University in Montreal and his
colleagues were the first to observe that cathelicidin production is ramped
up by vitamin Dor, more specifically, by the hormone 1,25-D, the vitamin's
active form (SN: 10/9/04, p. 232:
http://www.sciencenews.org/articles/20041009/bob8.asp
<http://www.sciencenews.org/articles/20041009/bob8.asp
of events, vitamin D transforms into a compound, called a prehormone, that
circulates in blood and then is converted locally, as needed, into 1,25-D.
In the nucleus of cells, 1,25-D binds to short sequences of DNA. Known as
response elements, these sequences switch on the activity 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 onjust 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 mean intuitive thoughtthat 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:
http://www.sciencenews.org/articles/20041016/bob9.asp
<http://www.sciencenews.org/articles/20041016/bob9.asp
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 cathelicidinand were less likely to
kill the germsthan 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 exposurein moderationmight 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 radiationjust enough to evoke some skin reddening the next
dayactivated 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.
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 impacteven 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."