Secrets of shingles revealed by new animal model
Researchers can now see how chickenpox virus behaves in human nerve cells
Ann Arviin
BY KRISTA CONGER
Most of us have a time bomb nestled inside our nerve cells, waiting for our immune system to falter in the face of age or disease.
If you’ve had chicken pox, you’re at risk for shingles – a painful nerve disorder that can make the slightest breeze or touch excruciating. People over the age of 80 have a one in five chance of being affected, and every passing year increases the risk.
There may be hope on the horizon, though. Medical center researchers have developed the first animal model to study how the culprit, the varicella-zoster virus, negotiates an uneasy truce with our nerve cells that can last for decades after the spotty childhood rash fades.
Further research may allow the scientists to modify an existing vaccine to make it less likely to spark a shingles flare-up, or even to improve the shingle-free odds of those of us already playing unwilling hosts to the virus.
Until now, research has been hampered by the fact that the virus is especially picky in its choice of hosts: holding out for real human nerve cells rather than settling for those of any garden-variety research animal. Those in a culture dish weren’t up to the task of mimicking an ongoing infection, either.
Then Stanford scientists, led by pathology professor Irving Weissman, MD, devised a way to incorporate human nerve cells into the brains of mice.
“We can now see the behavior of the virus in human neurons for the first time,” said Ann Arvin, MD, chief of pediatric infectious disease at Lucile Packard Children’s Hospital and professor of pediatrics and of microbiology and immunology.
Arvin is the senior author of the research, which was published online in the Proceedings of the National Academy of Sciences in early July.
The double whammy dished out by varicella-zoster virus makes it particularly important to understand the give-and-take between virus and host.
Although a modified, weakened version of the virus has been developed to protect healthy children against full-blown chicken pox, the vaccination can sometimes cause later episodes of shingles in children whose immune systems are compromised by cancer or organ transplantation. The risk of reactivation, however, is lower for vaccinated children than for those who were naturally infected with the wild-type virus.
“We can use this model to understand which viral genes are important for infecting neurons,” said Arvin. “If we can get rid of those genes in the virus used for the vaccine, we might be able to prevent reactivation.”
The researchers found that, as expected, the weakened virus used for the vaccine was capable of infecting the human neurons in the brains of the mice.
Once established, both the wild type and the vaccine version of the virus can also spread between neurons.
“We found that if the virus got into one cell, it seems to be able to infect nearby cells, presumably increasing its chances of reactivation,” said Arvin, who holds the Lucile Salter Packard Professorship in Pediatrics.
“It also behaves very differently in neurons than it does in skin cells: in skin it destroys the cells, whereas in neurons it seems to set up a kind of infection that allows it to persist for the lifetime of the individual,” she added.
The fact that the mice used in the study have non-functioning immune systems is also telling. It was previously thought that a robust immune response was the key to preventing an attack of shingles immediately after infection.
“Clearly all of this is taking place without any of the usual types of active immune responses,” said Arvin. “These findings suggest that the neuron itself has a way of accommodating the virus – a kind of temporarily mutually beneficial relationship that allows the neuron to escape destruction even while the virus persists.”