[afro-nets] People of African Descent and TB vulnerability

[Leela McCullough <leela@healthnet.org>]

People of African Descent and TB vulnerability
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Newly Identified Mechanism Helps Explain Why People Of African
Descent Are More Vulnerable To TB

http://www.medicalnewstoday.com/medicalnews.php?newsid=38463
28 Feb 2006

Boston, MA -- A team of scientists has identified a cellular
mechanism that may help explain the puzzle of why people of Af-
rican descent are more susceptible to tuberculosis infection and
why, once infected, they develop more severe states of the dis-
ease than whites. The team includes researchers from University
of California, Los Angeles (UCLA), and Harvard School of Public
Health (HSPH). The paper will appear online in the February 23
issue of Science Express.

Approximately eight million people worldwide are infected with
TB annually, with an estimated two million people dying from the
lung disease each year. TB is caused by the pathogen Mycobacte-
rium tuberculosis, but infection does not automatically result
in full-blown disease. In the U.S., minority and foreign-born
populations have significantly higher rates of TB than the over-
all U.S. average, according to the Centers for Disease Control
and Prevention. In 2004, African Americans had TB case rates
that were eight times higher than whites.

Scientists have understood that mice -- a frequently used animal
model in experiments -- combat microbes such as TB by producing
nitric oxide in scavenger cells of the immune system known as
macrophages. However, this mechanism is not prominent in humans,
and the mechanism by which human macrophages kill the tubercle
bacillus has remained an additional puzzle. Innate immunity is
the rapid immune response of host scavenger cells to recognition
of certain patterns of molecules found on pathogens, which has
been retained in evolution from fruit flies to humans. A set of
receptors on macrophages in humans called Toll-like receptors
contribute to innate immune responses. The researchers describe
a novel pathway used by human macrophages that may be critical
to resisting infection with certain pathogens and that turns out
to be critically dependent on vitamin D. This description pro-
vides a different way to think about how human immune systems
battle pathogens in general.

The research team found that when Toll-like receptors in humans
are stimulated by specific molecules of the tubercle bacillus,
vitamin D receptors and an enzyme called Cyp27B1, which converts
the vitamin from an inactive form to an active form, are dra-
matically increased. The result of this dual activation is the
cleavage of a preexistent protein to a small peptide called
cathelicidin, which can kill TB bacilli in the test tube. One of
the interesting aspects of this mechanism is that production of
vitamin D in humans is dependent on exposure to UV light, gener-
ally sunlight, and may not have evolved in mice since they are
nocturnal animals.

"These studies began with a very basic exploration of differ-
ences in gene expression in two related human white blood cell
types known to be involved in host responses to infection, and
concluded by revealing a new and potentially important human
mechanism for killing intracellular pathogens," said Philip Liu,
postdoctoral scholar in the Department of Immunology and Molecu-
lar Genetics at the David Geffen School of Medicine at UCLA and
co-lead author of the paper.

African Americans have significantly lower levels of vitamin D
in their blood serum than whites because higher levels of mela-
nin -- the pigment that provides color to skin absorbs UV light
and reduces African Americans' ability to produce vitamin D.
When the macrophages were stimulated by molecules of the tuber-
cle bacillus that trigger Toll-like receptors, the research team
found that cells cultured in serum provided by African Americans
produced 63 percent less of the microbe-killing cathelicin than
when cultured in serum from whites. Supplementing the serum from
African Americans with vitamin D precursor to a range found in
serum samples from whites boosted the induction of cathelicidin.

Scientists have long known that African Americans have less vi-
tamin D than whites and that they are more vulnerable to TB.
This study helps to resolve two of the puzzles of tuberculosis,
the differences between mice and human antibacterial mechanisms,
and the susceptibility of people of African and possibly Asian
descent to tuberculosis. The researchers suggest a need for
clinical trials to investigate the effect of vitamin D supple-
mentation.

"Our results indicate that we have much yet to learn about human
immune responses to infections. They also emphasize the impor-
tance of vitamin D in human immune responses, and suggest that
it is now important to learn how much vitamin D is optimal for
innate immunity, and how that can best be achieved through diet
or supplementation," said the senior investigator of these stud-
ies, Dr. Robert Modlin, Klein Professor of Dermatology and Pro-
fessor of Microbiology, Immunology and Molecular Genetics at the
David Geffen School of Medicine at UCLA.

"Tuberculosis is a devastating disease that strikes vulnerable
populations particularly hard," said immunologist Barry R.
Bloom, Dean of the Faculty at HSPH and a co-author of the paper.
"This study provides a new mechanism for innate immunity in hu-
mans and demonstrates how variations in vitamin D synthesis may
make individuals susceptible to TB infection. It is exciting to
consider the possibility that innate immunity to tuberculosis
and other infections in vulnerable populations might be enhanced
by providing a simple vitamin that would cost only pennies a
day."

--
This research was supported by grants from the National Insti-
tutes of Health and the German Research Foundation.

For further information contact:
Harvard School of Public Health
677 Huntington Avenue
Boston, MA 02115, USA
Contact: Robin Herman
mailto:rherman@hsph.harvard.edu

UCLA Health Sciences Media Relations
924 Westwood Blvd., Ste. 350
Los Angeles, CA 90095-7301, USA
Contact: Rachel Champeau
mailto:rchampeau@mednet.ucla.edu