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Newly identified mechanism helps explain why people of African descent are more vulnerable to TB

A team of scientists has identified a cellular mechanism that may help explain the puzzle of why people of African descent are more susceptible to tuberculosis infection and why, once infected, they develop more severe states of the disease 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 Mycobacterium 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 overall 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 provides a different way to think about how human immune systems battle pathogens in general.

< p>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 dramatically 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, generally sunlight, and may not have evolved in mice since they are nocturnal animals.

"These studies began with a very basic exploration of differences 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 Molecular 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 melanin -- 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 tubercle 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 vitamin 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 supplementation.

"Our results indicate that we have much yet to learn about human immune responses to infections. They also emphasize the importance 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 studies, Dr. Robert Modlin, Klein Professor of Dermatology and Professor 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 humans 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."


Source:Harvard School of Public Health

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