Study unveils how West Nile virus evades immune defenses, points to vaccine development
DALLAS – Oct. 3, 2006 -- West Nile virus evades the body's immune defenses by blocking immune signaling by a protein receptor, a finding that could pave the way for a vaccine to protect against North American strains of the virus, UT Southwestern Medical Center researchers report.
Researchers discovered the receptor's key role in controlling West Nile infection by conducting a study, described in October's Journal of Virology, that compares the genetics of an illness-causing Texas strain of the virus to a harmless African strain.
The Texas strain can inflict illness because it blocks the signaling activity of a protein receptor called the interferon alpha/beta receptor, or IFNAR, disrupting a cell's ability to direct the immune system to fight off the virus.
The African strain does not block IFNAR activity, so the immune system renders it harmless. The strain is harmful, however, in mice with dysfunctional receptors.
"We now hope to harness the African strain as the basis for West Nile vaccine studies. The virus has spread across the country and infected more than 2,100 U.S. residents – 180 in Texas this year alone, so we have to learn how to deal with it," said Dr. Michael Gale, associate professor of microbiology at UT Southwestern and director of the study. Brian Keller, a student in the Medical Scientist Training Program at UT Southwestern, is the first author of the study.
West Nile virus, which is transmitted by mosquito bite, arrived in the United States in 1999 and has become an epidemic that flares up in the summer and lasts into fall.
Infection causes mild flu-like symptoms in most people, but about one in every 150 develop serious illness, that can include high fever, coma, seizures and encephalitis and meningitis. Children, the elderly or people with weak immune systems are most at risk.
There is no vaccine. Doctors can only treat symptoms of the disease.
Searching for clues that might allow development of a vaccine, Dr. Gale and his research team compared one strain from each of West Nile's two basic categories: the harmful strains associated with outbreaks of encephalitis and meningitis in North America, and non-harmful strains from Madagascar and Cyprus.
They studied a harmful strain isolated from an infected grackle from Hall County, Texas, in 2002, and a harmless strain isolated from an infected parrot from Madagascar in 1978.
They mapped the genetic makeup of each strain, and then tested the viruses in mice.
West Nile infection triggers production of interferon, a group of proteins that are crucial in immune defense. Interferon, which binds to IFNAR, subsequently signals the JAK-STAT molecular pathway, a series of biochemical reactions essential for turning on immune-defense genes, allowing the body to clear out the virus. This process occurs normally in the African strain.
Infection by the Texas strain, however, blocked IFNAR signaling activity, allowing the virus to replicate and spread.
This highlights the integral role of interferon and IFNAR signaling in innate immunity.
Dr. Gale said the mechanisms at work in the African strain could be used as a basis for a vaccine, perhaps mutating North American strains so they no longer disrupt immune signaling. The remaining key is figuring out the exact mechanics of how the strains block signaling, a project Dr. Gale's team is already at work on.
Fortunately, North American strains are extremely similar – in fact, the one that appeared in the United States in 1999 and the Texas strain used in this study are 99 percent identical. One vaccine could, in theory, prevent illness from many of the harmful strains, Dr. Gale said.
"We feel a vaccine could be highly effective in preventing infection," said Dr. Gale.
Dr. Brenda Fredericksen of UT Southwestern and researchers from the Washington University School of Medicine, Texas Veterinary Medical Diagnostic Laboratory and UT Medical Branch in Galveston also were involved in the study.
The Ellison Medical Foundation, the National Institutes of Health and the Howard Hughes Medical Institute supported the study.
About UT Southwestern Medical Center
UT Southwestern Medical Center, one of the premier medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. Its more than 1,400 full-time faculty members – including four active Nobel prize winners, more than any other medical school in the world – are responsible for groundbreaking medical advances and are committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in 40 specialties to nearly 89,000 hospitalized patients and oversee 2.1 million outpatient visits a year.
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