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A Form of Interferon May Help Keep West Nile Virus from Getting into the Brain, A New Study Suggests

ARTICLE IN BRIEF

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INFECTION WITH THE WEST NILE virus (beige) causes inflammation that increases permeability of the blood-brain barrier (BBB), enabling the virus to penetrate the brain (top). However, as shown in the current study, the immune signaling molecule interferon-lambda (blue dots) strengthened and tightened the BBB, halting the spread of West Nile virus infection (bottom).

In a new study, investigators reported that interferon-lambda, an intracellular signaling protein, helps the blood-brain barrier stay tight, thus limiting the ability of the West Nile virus to infect the brain.

The cytokine interferon-lambda may help keep the West Nile virus from invading the brain, according to a study in mice published online April 22 in Science Translational Medicine.

The study, conducted at Washington University in St. Louis, does not conclude that interferon-lambda, an intracellular signaling protein, has a direct anti-viral effect, but rather suggests that it helps the blood-brain barrier stay tight, thus limiting the ability of the West Nile virus (WNV) to infect the brain. The study was done using mice bred to lack the receptor for interferon-lambda.

The findings may help explain why WNV infection has such variability in people, in many cases causing no symptoms and other times leading to severe neurologic damage, the study authors said. The findings could also prove useful in a broader way by furthering the understanding of how the blood-brain barrier (BBB) works and how it might be manipulated to either keep pathogens out or allow therapeutic drugs in.

“We can now look at this in the context of other viruses that get into the central nervous system,” said the study's senior coauthor, Michael S. Diamond, MD, PhD, who heads the Division of Infectious Diseases and Vaccine Development at the Center for Human Immunology and Immunotherapy Programs at Washington University School of Medicine.

About 70 to 80 percent of people infected with WNV, which is spread by mosquitoes, exhibit no obvious signs, while 20 percent develop symptoms that include fever, headaches, body aches, joint pain, nausea, vomiting, diarrhea, and rash. A fraction of infected persons, about 1 percent, develop neurologic complications such as encephalitis or meningitis, which can lead to altered mental status, limb weakness, and paralysis. Since there is no anti-viral treatment for WNV, care consists of treating the symptoms, including rehabilitative care to restore function. Recovery can take a long time and some neurologic problems may never resolve. About 10 percent of patients with neurologic complications end up dying.

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DR. MICHAEL S. DIAMOND said the findings on the relationship between interferon-lambda and the blood-brain barrier could have implications for developing treatments for other viruses that invade the brain.

“Because WNV is highly neurovirulent, the failure of infections to progress uniformly to neurologic disease suggest that barriers to neuroinvasion exist and that dissemination into the central nervous system (CNS) determines outcome,” according to background in the paper by the Washington University team.

“The precise mechanism by which WNV spreads to the brain and spinal cord remain unclear, but neuroinvasion likely occurs by a hematogenous route. Thus, the blood-brain barrier (BBB) represents a key defense against WNV neuroinvasion.”

STUDY METHODOLOGY

The researchers conducted a series of experiments using mice that lacked the interferon lambda-receptor. When they infected those mice and wild-type mice with WNV, they found that there was no difference between the two groups in the level of WNV in peripheral organs, such as the spleen and kidneys. But the mice lacking the interferon-lambda receptor had more WNV in their brains and spinal cord and the virus got there more quickly. The researchers next injected WNV directly into the brains of the defective mice and wild-type mice and found that the viral load in their brains were similar — a finding that suggested that interferon-lambda does not inhibit viral replication directly, but rather, through signaling, helps keep the BBB tight so that WNV has a harder time penetrating it.

To test their theory further, the researchers carried out a series of cell culture experiments — which involved an in vitro BBB model with brain endothelial cells from both mice and humans — in which they demonstrated that interferon-lambda influenced the integrity of the BBB. When WNV was introduced to cells from mice lacking the interferon-lambda receptor, the BBB cells were more permeable, allowing more virus to get in. In the normal mice, the BBB cells were less permeable.

In the final step of their experiment, the researchers infected wild-type mice with WNV and then administered soluble interferon-lambda. The treated mice had less WNV in their brains and more of the mice survived compared to control mice.

“The interferon-lambda did not inhibit virus in the peripheral organs, but it did inhibit virus from getting into the central nervous system,” Dr. Diamond said. He said the findings on the relationship between interferon-lambda and the BBB could have implications for developing treatments for other viruses besides WNV that invade the brain. He added they might also be useful in developing therapies for autoimmune diseases such as multiple sclerosis, in which immune cells get into the brain and do damage.

EXPERTS COMMENT

Ken Tyler, MD, FAAN, the Reuler-Lewin family professor and chairman of neurology at the University of Colorado Denver, said the Washington University study points to a “novel mechanism for the action of interferon lambda.

“The study very convincingly shows that this cytokine has an effect on maintaining the integrity of the blood-brain barrier,” Dr. Tyler told Neurology Today, “and that lack of blood-brain barrier integrity contributes to neuroinvasion by the virus.”

Dr. Tyler, an associate editor of Neurology Today, said efforts to develop a therapy or vaccine for WNV has been frustrating. Early clinical trials were conducted on four vaccines, he said, but there are no indications that any pharmaceutical company plans to take a vaccine into phase 3 testing. He said it would be difficult to decide where to set up for large-scale testing of a WNV vaccine because it is hard to predict where disease outbreaks will occur.

West Nile virus was first detected in the United States in 1999 and outbreaks in varying magnitude have occurred every summer since then. According to the Centers for Disease Control and Prevention, there were 2,122 reported human cases of West Nile virus in 2014. Of those, 60 percent were classified as neuroinvasive disease and 40 percent were classified as non-neuroinvasive.

John Morrey, PhD, a research professor and director of the Institute of Antiviral Research at Utah State University, said one of the therapeutic challenges that needs to be overcome with WNV is that most people don't seek medical attention until after the virus has already invaded the CNS. Even if interferon-lambda were proven to be effective, “it's a matter of therapeutic window. What therapeutic opportunity do you have once a person has West Nile disease?” he asked.

Avindra Nath, MD, chief of the Section of Infections of the Nervous System and Clinical Director at the National Institute of Neurological Disorders and Stroke, told Neurology Today that the Washington University research “is a very good study, but it is very preliminary. There would be a lot more work to do before this has any clinical applications.”

Dr. Nath said the study results raise some questions, including why there was an inconsistent effect when the mice were given interferon-lambda. WNV titers were lower in the cerebral cortex for the treated animals, but not in the cerebellum and spinal cord.

“They are not getting consistent results,” Dr. Nath said. “Why would interferon-lambda protect the cortex but not the other parts of the central nervous system?” More work remains to be done, he said.

EXPERTS: ON PREVENTING WEST NILE VIRUS FROM GETTING INTO THE BRAIN

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DR. KEN TYLER: “The study very convincingly shows that this cytokine has an effect on maintaining the integrity of the blood-brain barrier, and that lack of blood-brain barrier integrity contributes to neuroinvasion by the virus.”

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DR. JOHN MORREY said one of the therapeutic challenges that needs to be overcome with West Nile virus is that most people dont seek medical attention until after the virus has already invaded the CNS. Even if interferon-lambda were proven to be effective, “its a matter of therapeutic window. What therapeutic opportunity do you have once a person has West Nile disease?”

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DR. AVINDRA NATH said the study is good, but it is very preliminary. He noted that the study results raise some questions, including why there was an inconsistent effect when the mice were given interferon-lambda. West Nile virus titers were lower in the cerebral cortex for the treated animals, but not in the cerebellum and spinal cord.

LINK UP FOR MORE INFORMATION:

•. Lazear HM, Daniels BP, Pinto AK, et al. Interferon-λ restricts West Nile virus neuroinvasion by tightening the blood-brain barrier http://stm.sciencemag.org/content/7/284/284ra59. Sci Transl Med 2015;7(284):284ra59.
•. Centers for Disease Control and Prevention site on West Nile virus: http://www.cdc.gov/westnile/