Caging a bird

As a youth in southern Alabama, Carson Moseley (’09) fantasized about one day making medical discoveries that could aid those with elusive maladies like autism and diabetes, both of which his brother Everett suffered from. One researcher he especially hoped to emulate was Peter Doherty, who was awarded the Nobel Prize in Medicine in 1996.

Just as serendipity plays an indispensable role in biomedical discovery, so too did it help bring Moseley to a research center where he not only met Doherty, but also worked with a group — featuring three other Wake Forest graduates — that has discovered a promising approach to reducing mortality in a flu pandemic.

In a paper published in the prestigious Proceedings of the National Academy of Science, Moseley and nine other researchers at St. Jude Children’s Research Hospital in Memphis — including Jerry Aldridge Jr. (PhD ’06), Paul Thomas (’99) and Nicholas Negovetich (MS ’03, PhD ’07) — describe their isolation of a cell specific to the immune system’s reaction to infection by virulent strains of flu virus and their identification of a drug that could help prevent the cell’s massive reaction to such viruses from killing the patient.

Ever since the Spanish Flu pandemic of 1918 afflicted 500 million and killed as many as 100 million worldwide, public health officials have feared the emergence of another strain that would have similarly dire consequences. In recent years they have kept a wary eye on the so-called avian, or bird, virus and its various mutations as one with such potential.

Last summer, while Moseley was serving an internship at the hospital, the St. Jude team isolated a particular type of cell known as Tip-DC that the immune system produces to fight lung infection. When resisting a flu bug for which it has a natural antibody, the immune system responds in a modulated way, and the sick person generally gets better. But when an unfamiliar virus like avian flu (or, worse, an emerging avian-swine flu mutation) invades the lungs, the system dispatches Tip-DC cells in quantities so massive that potentially lethal inflammation results, according to the team’s findings. People seemingly are killed not by the virus, but by their immune system’s attack of it.

The solution, it would seem, would be to suppress the Tip-DC. The immune system, however, is highly complex, with many interconnected variables, and suppression of one of its components can cause it to malfunction. Besides, as it turns out, Tip-DC cells are needed in a later phase of the immune system’s response to the viral invasion. When it comes to Tip-DC cells, you can’t live with them, and you can’t live without them.

The St. Jude team identified an insulin-resistance inhibiting drug called pioglitazone that has moderating effects on the immune system. By administering the drug to laboratory mice and exposing the mice to virulent flu viruses, the researchers documented substantial reductions in the accumulation of Tip-DCs in the lungs and a drop in the rate of inflammation-related mortality from 90 percent to 50 percent. The findings raised the possibility that pretreatment with pioglitazone could save millions of lives in a flu pandemic.

At Wake Forest, Moseley worked in the lab of William Louis Poteat Professor of Biology Raymond E. Kuhn (P ’94), an immunologist, as did Thomas when he was an undergraduate a decade ago before earning his doctorate at Harvard. Kuhn was so impressed with Moseley’s talents that he helped arrange his internship at St. Jude by contacting Aldridge, whose doctoral studies Kuhn had overseen. Negovetich earned his doctoral degree at Wake Forest under the tutelage of Charles M. Allen Professor of Biology Gerald Esch (P ’84).

“The idea for using [pioglitazone] came from Carson, who knew about it from research he did at our medical center,” Kuhn said. “It was never designed to be used for an infectious disease but after working a while with [Aldridge] and looking at the immune responses of mice that had died from bird flu, he made the correlation. It is amazing that his first paper, as second author, was in [such an] extremely prestigious journal.”

Moseley is enrolled in medical school this fall at the University of Alabama at Birmingham. “I suspect that once Carson finishes his medical training,” Kuhn adds, “he will find a way to continue doing research.”

Categories: Research