Harnessing immune function to fight disease

By Ruth SoRelle, M.P.H.

Some day, scientists may be able to mount an attack against diseases such as tuberculosis by mustering an ancient immune function called autophagy, said researchers at Baylor College of Medicine in a recent report in the journal Immunity.

When stressed or starved, cells turn on autophagy which causes them to digest parts of themselves. The process also prompts the degradation of invading pathogens, which could prove important in future disease-fighting, said N. Tony Eissa, M.D., professor of medicine—pulmonology and immunology at BCM and the senior author of the study. His study helps explain the mechanism by which autophagy is turned on.

Autophagy destroys pathogens

"In the past few years, there has been increased interest in autophagy because the process is involved in destroying pathogens," said Eissa. What Eissa and his colleagues found was that lipopolysaccharides, an important part of the outer cell wall of certain types of bacteria, use an important receptor (Toll-like receptor 4) to turn on the autophagy pathway.

They also determined that that the signal from the receptor interacts with the proteins involved. This helps explain how autophagy defends against infection.

Mycobacteria survive by hiding

One important pathogen affected by autophagy is the one responsible for tuberculosis.

"We show that when macrophages (key cells in the immune system) are infected with Mycobacteria (which cause tuberculosis), the cells in which this pathway is turned on can trap the bacteria and destroy them.

"Mycobacteria are among the oldest and smartest pathogens," he said. "Even the mummies of the Egyptian pharaohs carried them. They survive by hiding inside the cells in pockets under the cell wall." This prevents them from moving down the pathway that leads to their destruction inside the cell.

"Somehow, the Mycobacteria evade that response by secreting a substance that inhibits autophagy," said Eissa.

Fake infection activates autophagy in Mycobacteria

By exposing the cells to lipopolysaccharides, he and his colleagues tricked the cells into thinking they were infected by something other than the TB-causing organism. That fake "infection" activated the autophagy response and enabled the cell to eliminate the Mycobacteria.

"Now we have a pathway we can target to stimulate host defense against pathogens. It is independent of antibiotics," he said. Resistance to antibiotics is a major concern in tuberculosis treatment.

Innate immunity, such as autophagy, is not specific for a particular organism, but it can hold off pathogens until more specific immune mechanisms take charge of the battle.

Autophagy could play important role during epidemics

"It is conceivable that during an epidemic, one could use this system of activating autophagy to enhance innate immunity in large populations of people until the more specific immune response or effective drugs can take over," he said. He plans to find out if the system works in influenza A or rhinoviruses.

The work may also help explain why some people become infected with pathogens while their friends do not, he said. It could also have implications in people with asthma or allergies who take longer time to clear up some infections.

Others who took part in the research include Drs. Yi Xu, Xian-De Liu, Amir Sharafkhaneh and Katarzyna E. Kolodziejska, all of BCM and Chinnaswarmy Jagannath of The University of Texas Health Science Center at Houston.

Funding for this work came from the National Heart, Lung and Blood Institute, the National Institute of Allergy and Infectious Diseases, the American Heart Association and the Alpha-1 Foundation.

An abstract of the article can be found at http://www.immunity.com/content/article/abstract?uid=PIIS1074761307003366&highlight=eissa

Visit the Medicine-Pulmonary site: http://www.bcm.edu/medicine/pulmonary/