Ancient Innate Immune Function could Help Fight TB

New understanding of how to turn on the process of autophagy, an ancient immune function that causes cells to digest parts of themselves when stressed or starved as well as promoting the degradation of invading pathogens, could provide clues to fighting wily viruses or bacteria, including the one that causes tuberculosis, said researchers at Baylor College of Medicine in Houston in a report that appears today in the journal Immunity.

“In the past few years, there has been increased interest in autophagy because the process is involved in destroying pathogens,” said Dr. N. Tony Eissa, 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.The key is in lipopolysaccharides, an important part of the outer cell wall of certain types of bacteria, that uses an important receptor (Toll-like receptor 4) to turn on the autophagy pathway, said Eissa. This understanding coupled with information about how the signal from the receptor interacts with the proteins involved explains how autophagy defends against infection.”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.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 defence 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.”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.(Source: Immunity : Baylor College of Medicine : September 2007)