TB Event Highlights Research and Honors Dean Bloom

HSPH Dean Barry R. Bloom was honored by colleagues at a special symposium, "Tuberculosis — Past Challenges and Promise," on Monday, May 5, 2008, in Snyder Auditorium. Dean Bloom will be stepping down from his position as the School's leader. He will become a Harvard University Distinguished Service Professor and will continue his research and other activities related to global health as a member of the HSPH faculty. Dyann Wirth, chair of the Department of Immunology and Infectious Diseases, welcomed attendees.

"It took a catalyst like Barry to get the field to where it should be," said Eric Rubin, associate professor of immunology and infectious diseases at HSPH. Rubin credited Dean Bloom's advocacy and research two decades ago, at a time of rising U.S. and global TB incidence, as a major force for the sharp increase in U.S. funding for TB research around 1990. "The benefits of the research have yet to be realized, but there are exciting things happening now," he said.

Symposium talks ranged from discussions of host immunology to bacterial genetics to epidemiology. Each speaker trained or collaborated with Dean Bloom. Citing Dean Bloom's guiding example, they shared new findings that challenged some assumptions in the field.

Worldwide, one out of every three people is infected with TB. Typically, the bacteria remain harmless, sequestered in clusters of immune cells, or granulomas, in the lungs. But in about 10 percent of cases, the disease reactivates.

"The real battlefield is the granuloma, and the host usually wins," said JoAnne Flynn in the opening talk. Flynn has developed a monkey model to study TB because mice do not develop the latent stage of the disease so common in people. About half the exposed monkeys develop a latent TB, and all show human-like pathology and disease variability, said Flynn, professor of immunology at the University of Pittsburgh School of Medicine. Preliminary studies seem to confirm the importance of key protective immune factors first identified in mice by Flynn and others, such as CD8 T cells and tumor necrosis factor, although they probably work by different molecular mechanisms. Other data cast doubt on the necessity of CD4 T cells in restraining the bacteria, at least in some animals.

Reactivating a line of investigation once thought to be a dead end, John Chan reported that B cells may play a protective role, possibly in modulating the granuloma response. He said that B cells also can affect the development of CD4 and CD8 T cells by another mechanism. Chan is another Bloom lab alumnus and professor of microbiology and immunology and of medicine at Albert Einstein College of Medicine. 

In the lungs, granulomas form when other immune cells swarm to the defense of macrophages, the cell invaded by TB. Robert Modlin, a longtime Bloom collaborator at University of California, Los Angeles, has discovered a possible way to help macrophages singlehandedly kill their TB intruders: increase the body's stores of vitamin D.
Human macrophages can kill invasive TB bacteria, but not in the way mouse macrophages do, researchers in Modlin's lab found. Further work revealed that macrophages kill TB via the vitamin D pathway. At the end of the line, the vitamin D receptor activates an antimicrobial molecule called cathelicidin.

One of the major unanswered puzzles in TB has been why people of African and Asian descent have higher susceptibility to the disease, and, when infected, suffer a more severe course. Few people can get enough sunlight naturally to provide the key raw material, vitamin D, to fuel antimicrobial activity. But the problem is compounded in African Americans, who require about 10 times as much ultraviolet light to produce the same amount of vitamin D.

The potentially therapeutic doses of vitamin D start at least five times higher than the current 400 mg recommended daily by the U.S. Food and Drug Administration, said Modlin. He and his colleagues hope to test the effect of vitamin D on the immune response of healthy people and are planning a clinical trial in Tanzania with HSPH investigators to study the impact on TB.

Sarah Fortune, assistant professor of immunology and infectious diseases at HSPH, has launched a whole-genome analysis of Mycobacterium tuberculosis to find genetic roots of functional diversity, including mutations or gene swaps that bestow drug resistance. So far, it appears that polymorphisms in a very small subset of genes can generate considerable functional diversity, said Fortune, who helped organize the symposium and who has worked with Dean Bloom's lab.

Megan Murray, associate professor of epidemiology at HSPH, posed an important question. A string of studies that began with a 1994 report by Dean Bloom and his colleagues has indicated that at least 40 percent of TB cases — and two-thirds of drug-resistant cases — at a major Bronx, New York, hospital, arose from newly transmitted infections. The finding overturned a presumption that most TB cases arose from activation of latent infection. "The question is, how much does latency have to do with TB transmission?" she said.

Adrie Steyn, assistant professor in the Department of Microbiology, University of Alabama at Birmingham, and John McKinney, professor at the Global Health Institute in the School of the Life Sciences at the Ecole Polytechnique Fédérale de Lausanne, also spoke.

The event was sponsored by the Department of Immunology and Infectious Diseases and the Global Infectious Diseases Program, Harvard Initiative for Global Health.

—Carol Cruzan Morton. Image from CDC/Dr. Ray Butler; Janice Carr.