A virus that most people have probably never heard of, yet most of us carry, is the number 1 infectious cause of congenital birth defects. One in 750 children are born with, or develop, permanent disabilities such as hearing loss or brain damage as a result of CMV (cytomegalovirus) infection in the womb. Major research efforts are underway to combat this invidious disease.
Researchers from Cardiff University and the La Jolla Institute, California, have discovered a previously unknown cellular mechanism that could prove critical in creating a CMV vaccine.
"CMV is recognised as a major pathogen by Clinicians, yet there is little public awareness of the virus." says Professor Gavin Wilkinson from the Cardiff University School of Medicine. "More children have disabilities from this disease than other well-known congenital problems, such as Down's syndrome or fetal alcohol syndrome."
"We have identified a novel trick that this virus uses to hide from immune detection," says La Jolla Institute scientist Chris Benedict, Ph.D., a CMV expert. "By uncovering this mechanism, we've provided an important piece of the CMV puzzle that could enable vaccine counter strategies that flush out and eliminate virus-infected cells." The finding was published online today in the journal Cell, Host & Microbe.
CMV's stealthy nature keeps it under wraps. In common with other member of the herpes family of viruses that cause cold sores, chicken pox and other maladies - once contracted, CMV never goes away. Most people are unaware they have contracted the virus, nor generally do they exhibit any visible symptoms during lifelong carriage. However, research is now revealing how hard that the immune system has to fight to keep CMV at bay.
"In addition to causing terrible birth defects and severe disease in patients with autoimmune disease, CMV induces changes in the immune response of anyone carrying the virus," according to Professor Wilkinson. The constant struggle to control CMV contributes to the immune system 'tiring' over time.
In their study, researchers found that a specific CMV gene (called UL141) blocks the ability of two key immune pathways to kill CMV-infected cells. As their names imply, these two pathways - known as TRAIL "death receptor" 1 and 2 - normally act to kill infected cells.
TRAIL death receptors have already been actively targeted in anti-tumor therapies. While important in cancer, it has also become quite clear that TRAIL signaling by the immune system is very significant in viral infections, such as CMV. By illuminating the UL141 gene as inhibiting TRAIL's ability to carry out its killing function, the researchers believe they have identified a pivotal cellular defence that needs to be considered when developing an effective vaccine.
The TRAIL molecule and its receptors were discovered about 15 years ago and are members of the tumor necrosis factor family of molecules, which have proven extremely important in medical research efforts to control or prevent many diseases. The research team was the first to identify a herpes virus function (UL141) interacting with the TRAIL Death receptors, and it is only the second known protein known to do so (TRAIL is the other).
Ed Mocarski, Ph.D., a scientist at the Emory University School of Medicine's Vaccine Center, praised the discovery for identifying some of the key cells involved in the ongoing tug-of-war between CMV and the immune system. "This finding puts on the table the importance of TRAIL signaling in host (our body's) defense and how the virus works to block these efforts," says Dr. Mocarski, whose research focuses on new ways to combat CMV. "This knowledge could set the stage for developing ways to boost the adaptive immune response which could ultimately aid in developing an effective vaccine."
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