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Shorter colds, milder flu may follow from newly revealed immune mechanism

Enlisted to help fight viral infections, immune cells called macrophages consume virus-infected cells to stop the spread of the disease in the body. Now researchers at Washington University School of Medicine in St. Louis have uncovered how macrophages keep from succumbing to the infection themselves. Boosting this mechanism may be a way to speed recovery from respiratory infections.

The researchers found that a specific protein produced in the course of respiratory viral infections can serve to protect macrophages from an untimely death. Their report will appear in an upcoming issue of Nature Medicine and is available on October 9 at the journal's website.

"If the macrophages were to die, the infection would spread further," says senior author Michael J. Holtzman, M.D., the Selma and Herman Seldin Professor of Medicine and director of pulmonary and critical care medicine. "So the macrophages use a protein called CCL5 to ensure that the infection process can be stopped before it goes any further."

Holtzman thinks the information about the role of CCL5 may lead to new methods to hasten recovery from respiratory viral inflections like influenza or the common cold, which at present have no pharmacological cure.

CCL5's role was discovered while Holtzman's group was testing mice that had respiratory infections. They found that the sick mice produced massive amounts of CCL5--about a hundred times more than they produced when healthy.

"CCL5 was just off the chart compared to the other 30,000 mouse genes," Holtzman says. "Then the challenge was to figure out why CCL5 gene expression should be so far above everything else."

They found that mice lacking the gene to make CCL5 died much more frequently from respiratory virus infection than normal mice. Examining lung tissues from these CCL5-deficient mice, the researchers saw that macrophages--which would ordinarily enter the airway, clean up virus-infected cells and then leave-- remained stuck in the airway tissue. It became apparent that the macrophages were unable to leave because they were infected with virus and so were dying prematurely.

Unexpectedly, the investigators found that CCL5 turns on signals that allow cells to escape virus-induced death. These signals are termed anti-apoptotic because they work against a process of programmed cell death called apoptosis. The CCL5-induced anti-apoptotic signals therefore help keep macrophages alive, which allows them to continue their job in the face of a viral onslaught.

"CCL5's role is somewhat of a paradox," Holtzman says. "Ordinarily, apoptosis is a protective mechanism. Death of infected lung airway lining cells, or epithelial cells, would deprive the virus of its home and protect the host against the spread of infection. But in the case of the macrophage, it is the opposite. Preventing the death of the macrophage allows the host to ultimately clear the viral debris and so finally halt the infection. Balancing these cell death and survival pathways can determine whether the virus or the host wins the battle."

Next, the researchers will look further at precisely how CCL5 prevents cell death.

"In this initial study, we identified the cellular receptor for CCLR and some of the first downstream signals that convey a survival message," Holtzman says. "Now, we aim to define more specific signaling proteins that allow the cell to live or die in the face of infection. Identifying these signals may allow us to regulate these signals during an infection, and so make epithelial cells and macrophages more effective to shorten recovery time or lessen symptoms."

The ability to decrease the severity of lung infections may also have important implications for asthma, COPD (chronic obstructive pulmonary disease) and other chronic lung diseases, according to Holtzman.

"We commonly see children, for example, who develop these same types of severe respirato ry infections as infants and then go on to develop asthma later," Holtzman says. "If we can improve the outcome from this first interaction with the viruses, we are very likely to also prevent the later development of persistent airway disease."


Source:Washington University School of Medicine

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