St. Louis, Oct. 9, 2005 -- Enlisted to help fight viral infections,immune cells called macrophages consume virus-infected cells to stopthe spread of the disease in the body. Now researchers at WashingtonUniversity School of Medicine in St. Louis have uncovered howmacrophages keep from succumbing to the infection themselves. Boostingthis mechanism may be a way to speed recovery from respiratoryinfections.
The researchers found that a specific protein produced in the courseof respiratory viral infections can serve to protect macrophages froman untimely death. Their report will appear in an upcoming issue ofNature Medicine and is available on October 9 at the journal's website.
"If the macrophages were to die, the infection would spreadfurther," says senior author Michael J. Holtzman, M.D., the Selma andHerman Seldin Professor of Medicine and director of pulmonary andcritical care medicine. "So the macrophages use a protein called CCL5to ensure that the infection process can be stopped before it goes anyfurther."
Holtzman thinks the information about the role of CCL5 may leadto new methods to hasten recovery from respiratory viral inflectionslike influenza or the common cold, which at present have nopharmacological cure.
CCL5's role was discovered while Holtzman's group was testing mice thathad respiratory infections. They found that the sick mice producedmassive amounts of CCL5--about a hundred times more than they producedwhen 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 geneexpression should be so far above everything else."
They found that mice lacking the gene to make CCL5 died muchmore frequently from respiratory virus infection than normal mice.Examining lung tissues from these CCL5-deficient mice, the researcherssaw that macrophages--which would ordinarily enter the airway, clean upvirus-infected cells and then leave--remained stuck in the airwaytissue. It became apparent that the macrophages were unable to leavebecause they were infected with virus and so were dying prematurely.
Unexpectedly, the investigators found that CCL5 turns onsignals that allow cells to escape virus-induced death. These signalsare termed anti-apoptotic because they work against a process ofprogrammed cell death called apoptosis. The CCL5-induced anti-apoptoticsignals therefore help keep macrophages alive, which allows them tocontinue 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 airwaylining cells, or epithelial cells, would deprive the virus of its homeand protect the host against the spread of infection. But in the caseof the macrophage, it is the opposite. Preventing the death of themacrophage allows the host to ultimately clear the viral debris and sofinally halt the infection. Balancing these cell death and survivalpathways 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 forCCLR and some of the first downstream signals that convey a survivalmessage," Holtzman says. "Now, we aim to define more specific signalingproteins that allow the cell to live or die in the face of infection.Identifying these signals may allow us to regulate these signals duringan infection, and so make epithelial cells and macrophages moreeffective to shorten recovery time or lessen symptoms."
The ability to decrease the severity of lung infections mayalso have important implications for asthma, COPD (chronic obstructivepulmonary disease) and other chronic lung diseases, according toHoltzman.
"We commonly see children, for example, who develop these same types ofsevere respiratory infections as infants and then go on to developasthma later," Holtzman says. "If we can improve the outcome from thisfirst interaction with the viruses, we are very likely to also preventthe later development of persistent airway disease."
Tyner JW, Uchida O, Kajiwara N, Kim EY, Patel AC, O'Sullivan MP,Walter MJ, Schwendener RA, Cook DN, Danoff TM, Holtzman MJ. CCL5/CCR5interaction provides anti-apoptotic signals for macrophage survivalduring viral infection. Nature Medicine, available online Oct. 9, 2005.
Funding from the National Institutes of Health (Heart, Lung and Blood Institute) supported this research.
Washington University School of Medicine's full-time andvolunteer faculty physicians also are the medical staff ofBarnes-Jewish and St. Louis Children's hospitals. The School ofMedicine is one of the leading medical research, teaching and patientcare institutions in the nation, currently ranked third in the nationby U.S. News & World Report. Through its affiliations withBarnes-Jewish and St. Louis Children's hospitals, the School ofMedicine is linked to BJC HealthCare.
Materials provided by Washington University School of Medicine. Note: Content may be edited for style and length.
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