Vitamin D and infection

November 14, 2006

http://www.sciencenews.org/articles/20061111/bob9.asp

http://www.sciencenews.org/articles/20061111/bob9.asp>

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. 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.

" 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, 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 for the December Epidemiology and Infection.

This is only a hypothesis, " but a very credible one " that deserves

testing, says immunologist Zasloff of town 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 substances—like 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 munitions—cathelicidin. Dermatologist and

immunologist 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 H. White of McGill University in Montreal

and

his colleagues were the first to observe that cathelicidin production

is

ramped up by vitamin D—or, 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). Through a

cascade 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 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 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). 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.

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. "

References:

Braff, M.H. . . . and R.L. Gallo. 2005. Cutaneous defense mechanisms

by

antimicrobial peptides. Journal of Investigative Dermatology

125(July):9-13. Available at

http://dx.doi.org/10.1111/j.0022-202X.2004.23587.x.

Cannell, J.J., et al. 2006. Epidemic influenza and vitamin D.

Epidemiology and Infection 136(December):1129-1140. Abstract and

preprint available at http://dx.doi.org/10.1017/S0950268806007175.

Chromek, M. . . . R.L. Gallo, et al. 2006. The antimicrobial

cathelicidin protects the urinary tract against invasive bacterial

infection. Nature Medicine 12(June):636-641. Available at

http://dx.doi.org/10.1038/nm1407.

Gombart, A.F., Q.T. Luong, and H.P. Koefler. In press. Vitamin D

compounds: Activity against microbes and cancer. Anticancer Research.

Abstract.

Gombart, A.F., N. Borregaard, and H.P. Koeffler. 2005. Human

cathelicidin antimicrobial peptide (CAMP) gene is a direct target of

the

vitamin D receptor and is strongly upregulated in myeloid cells by

1,25-dihydroxyvitamin D3. FASEB Journal 19(July):1067-1077. Available

at

http://www.fasebj.org/cgi/content/full/19/9/1067.

Howell, M.D. . . . R.L. Gallo, et al. 2004. Selective killing of

vaccinia virus by LL-37: Implications for eczema vaccinatum. Journal

of

Immunology 172(Feb. 1):1763-1767. Available at

http://www.jimmunol.org/cgi/content/full/172/3/1763.

Liu, P.T., et al. 2006. Toll-like receptor triggering of a vitamin

D-mediated human antimicrobial response. Science 311(March

24):1770-1773. Abstract available at

http://www.sciencemag.org/cgi/content/abstract/311/5768/1770.

López-García, B., P.H.A. Lee, and R.L. Gallo. 2006. Expression and

potential function of cathelicidin antimicrobial peptides in

dermatophytosis and tinea versicolor. Journal of Antimicrobial

Chemotherapy 57(May):877-882. Abstract available at

http://dx.doi.org/10.1093/jac/dkl078.

Mallbris, L. . . . and M.M. Ståhle. 2005. UVB upregulates the

antimicrobial protein hCAP18 mRNA in human skin. Journal of

Investigative Dermatology 125(November):1072-1074. Available at

http://www.nature.com/jid/journal/v125/n5/full/5603631a.html.

Muhe, L., et al. 1997. Case-control study of the role of nutritional

rickets in the risk of developing pneumonia in Ethiopian children.

Lancet 349(June 21):1801-1804. Abstract available at

http://dx.doi.org/10.1016/S0140-6736(96)12098-5.

Murakami, M. . . . and R.L. Gallo. 2005. Expression and secretion of

cathelicidin antimicrobial peptides in murine mammary glands and

human

milk. Pediatric Research 57(January):10-15. Available at

http://www.pedresearch.org/cgi/content/full/57/1/10.

Wang, T.-T. . . . and J.H. White. 2004. Cutting edge:

1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide

gene expression. Journal of Immunology 173(Sept. 1):2909-2912.

Available

at http://jimmunol.org/cgi/content/full/173/5/2909.

Weber, G. . . . and M. Ståhle. 2005. Vitamin D induces the

antimicrobial

protein hCAP18 in human skin. Journal of Investigative Dermatology

124(May):1080-1082. Available at

http://dx.doi.org/10.1111/j.0022-202X.2005.23687.x.

Zasloff, M. 2006. Fighting infections with vitamin D. Nature Medicine

12(April):388-390. Abstract available at

http://dx.doi.org/10.1038/nm0406-388.

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