Could something as simple and inexpensive as a vitamin pill boost resistance to Mycobacterium tuberculosis, one of the most formidable and deadliest pathogens on Earth? It's an idea not to be dismissed, say immunologists from the University of California, Los Angeles (UCLA) and the Harvard School of Public Health (HSPH). In the March 6 issue of Science, they have published a study that may help explain why people of African descent--and perhaps also others of color, including Asians--have long been known to be more vulnerable to TB than whites.

The possible key to their susceptibility? A deficit in vitamin D.

The tubercle bacillus infects about one in three people worldwide, according to the World Health Organization (WHO). While in most people the microbe either lies dormant for years or is killed quickly by first-line immune defenses, it also causes nearly 9 million cases of active infection and more than 2 million deaths, according to WHO estimates. People of African descent have been known to develop active TB far more readily than whites do, and their disease, if untreated, is also generally more severe. In the United States, according to the Centers for Disease Control and Prevention, TB case rates for African Americans are about eight times higher than they are for whites.

The new study found that the body's "innate" immune response to infection--a swift, first-line defense against a variety of pathogens by immune scavenger cells called macrophages--is critically dependent on vitamin D. The body makes vitamin D when the sun's ultraviolet rays hit the skin. But in dark-complexioned populations, the skin pigment, melanin, absorbs those rays, lowering vitamin D levels in the blood.

TB IN BLACK AND WHITE

Of the world's 22 highest-burden TB countries, nine are in Africa, according to the World Health Organization (WHO). They are: Democratic Republic of Congo, Ethiopia, Kenya, Mozambique, Nigeria, South Africa, Uganda, United Republic of Tanzania, and Zimbabwe. These countries face huge challenges related to the HIV/AIDS epidemic, which greatly weakens the immune system and heightens the risk of infection and death caused by TB.

The largest number of new TB cases in 2004 occurred in WHO's 11-country South-East Asia Region, which accounted for 33 percent of incident cases globally. However, the estimated incidence per capita in sub-Saharan Africa is now nearly twice that of the South-East Asia Region, approaching 400 cases per 100,000 people.

In the United States, non-Hispanic blacks accounted for 28 percent of new TB cases in 2003. They also accounted for the highest percentage of TB cases in the U.S.-born population--44 percent--and 13 percent of cases among the foreign-born.

"In populations vulnerable to TB, it's exciting to consider the possibility that innate immunity might be enhanced by a vitamin costing just pennies a day," says HSPH Dean Barry Bloom, a study co-author and the Joan L. and Julius H. Jacobson II Professor of Public Health.

"This study shows how variations in vitamin D synthesis may make some individuals susceptible to TB," says Bloom. "It also reveals a new mechanism by which the innate immune response--conserved through evolution, from fruit flies to mice to humans--battles certain pathogens."

A mystery fathomed
In 1992, a team led by Bloom discovered how macrophages killed M. tuberculosis in laboratory mice: by producing nitric oxide. So scientists began hunting for a similar mechanism in human immune cells in test tube studies. They and many other scientists searched and searched, but the quest proved disappointing.

Then a breakthrough came, in 2005, in the laboratory of Robert Modlin, a professor of dermatology and microbiology, immunology, and molecular genetics at UCLA and a longtime collaborator of Bloom's. In Modlin's lab, a postdoctoral scholar named Philip Liu and his co-workers began genetically screening two related types of human white cells to see which genes were switched "on" and "off" when the cells encountered M. tuberculosis. Only in the macrophages capable of killing the tubercle bacillus did they find that the major switched-on gene encoded the receptor molecule for vitamin D.

Suddenly, the researchers were on the way to uncovering a new mechanism for killing the tubercle bacillus--a mechanism that bore no resemblance to the one they and others had demonstrated in mice, and that had been implicated previously in destroying other microbes.
In the test tube, the research team found that the interaction between surface molecules on the bacterium and the macrophage triggered a chain of events within the immune scavenger cell: a dramatic increase in vitamin D receptors and production of an enzyme that converted vitamin D to its active form. Both steps proved crucial to the genesis of a protein fragment, cathelicidin, that can destroy M. tuberculosis, an otherwise tough, resilient pathogen.

The UCLA-HSPH collaborators offer a tantalizing explanation for why scientists' hunt for similar TB-killing mechanisms in mice and men has not panned out. Humans, who are active by day, may have evolved the ultraviolet-light-and-vitamin-D pathway to kill microbes inhaled in small numbers. Mice, being nocturnal and not exposed in nature to the tubercle bacillus, depend primarily on a different pathway to resist pathogens.

Next, the researchers compared the response to M. tuberculosis of immune cells from blood serum donated by African Americans and whites. After confirming that the sera from African Americans had lower levels of vitamin D, they cultured macrophages from it and discovered, first, that the cells made 63 percent less cathelicidin than cells cultured from the sera of white donors; and second, that these cells were ineffective in killing the TB pathogen. Moreover, bringing the vitamin D precursor in African American serum up to the levels seen in Caucasian serum sparked production of microbicidal cathelicidin by the macrophages.

Bloom says the newfound mechanism may explain the historic link between TB resistance in humans and sunlight. Starting in the late 1800s, sunlight and fresh air were thought to help cure active TB, which led to the great sanatorium movement. Wheeling patients' beds out onto these institutions' sunlit porches gave way to effective antibiotics in the mid-20th century, Bloom says, "but our research shows that the idea may not have been totally crazy. It's unfortunate that sanatoria later installed windows, since glass filters out ultraviolet rays."

If the studies in the laboratory help explain the increased susceptibility of people in Africa and Asia to tuberculosis, Bloom says, they also raise difficult questions about the role of race as a factor in disease susceptibility.

"Race is a very vague concept, hard to define in any scientific way," he says. "From human genetic studies, it is clear that there are greater genetic differences between any two individuals than between any classification of races. In the case of skin pigmentation, it is important to point out that essentially all of us have melanin pigment in skin organelles called melanosomes."
Based on the Science study, Bloom says, "Differences between Africans, Asians, and European populations that might relate to susceptibility to tuberculosis are essentially quantitative--a matter of how much melanin they make--not qualitative."

The study's results are currently limited to the lab, Bloom cautions. But he believes they may be promising enough to warrant a clinical trial of vitamin D supplementation in Africa or Asia. For high-risk populations in the developing world, he says, the possibility that a simple, inexpensive vitamin pill might boost innate resistance to developing TB--one of humankind's oldest, most resilient foes--is an intriguing idea worth testing.

Of the world's 22 highest-burden TB countries, nine are in Africa, according to the World Health Organization (WHO). They are: Democratic Republic of Congo, Ethiopia, Kenya, Mozambique, Nigeria, South Africa, Uganda, United Republic of Tanzania, and Zimbabwe. These countries face huge challenges related to the HIV/AIDS epidemic, which greatly weakens the immune system and heightens the risk of infection and death caused by TB.

The largest number of new TB cases in 2004 occurred in WHO's 11-country South-East Asia Region, which accounted for 33 percent of incident cases globally. However, the estimated incidence per capita in sub-Saharan Africa is now nearly twice that of the South-East Asia Region, approaching 400 cases per 100,000 people.

In the United States, non-Hispanic blacks accounted for 28 percent of new TB cases in 2003. They also accounted for the highest percentage of TB cases in the U.S.-born population--44 percent--and 13 percent of cases among the foreign-born.

Karin Kiewra is editor of the Review and associate director of Development Communications.


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