Fred Hutch scientists identify new nerve growth factor

SEATTLE — June 29, 2017 — Scientists at Fred Hutchinson Cancer Research Center have discovered that a herpes virus causes skin cells to churn out a protein with an unusual and rare effect: It promotes nerve growth.

Although the human body can produce up to one million different kinds of proteins, only a handful have been shown to be nerve growth factors, or neurotrophins. The researchers hope this one, interleukin-17c, might someday be harnessed to repair nerve damage found in patients suffering from peripheral neuropathy, one of the most common side effects of chemotherapy.

“Hopefully, we’ve found a substance that naturally repairs neurons — that does it silently, every day, in every human being on Earth,” said Dr. Larry Corey, who heads the laboratory in the Hutch’s Vaccine and Infectious Disease Division where the research was conducted. “If that is truly what its main function is, and we can harness that function, we’re going to do something good for people.”

The findings, which were published today in the Journal of Experimental Medicine, were made by the husband and wife team of Drs. Tao Peng and Jia Zhu who for years have been carefully picking apart the molecular mechanics of herpes simplex virus type 2, the cause of genital herpes.

Human herpes simplex viruses infect and destroy skin cells, but then they retreat far from the infection site and lie dormant inside bunches of nerve-cell bodies called ganglia. When reactivated, they use the long fibers of nerves to move about.

Peng and Zhu found that interleukin-17c, also known as IL-17c, appears to operate as a chemical signal that protects and promotes the growth and branching of peripheral nerves. The herpes virus, in a sense, wants to keep those fibers healthy, because they are the roads these viral particles travel in search of new skin cells to infect.

 “It is a very smart virus,” said Peng, who has been studying herpes off and on since he emigrated as a student from Nanchang, China 27 years ago. He and Zhu moved in 2003 to Seattle, where they are affiliated with the University of Washington as well as Fred Hutch.

Zhu admits to a fascination with studying herpes. “In a tiny piece of tissue, there are a lot of secrets just hiding there, waiting for us to discover,” she said. “There are a lot clues.”

A few years ago, while the two were working together to probe the microenvironment where the virus infects skin, Peng first noticed that skin cells were producing IL-17c, a protein that previously had been suspected of causing inflammation in the skin disease, psoriasis.

She connected this discovery of IL-17c with an observation she had made years earlier  about herpes infection in humans, but had not pursued: Nerve fibers in patients with active herpes infections appeared longer and denser. Could there be a link to IL-17c? Their experiments began to show that nerve cells grew in the presence of it. But why?

It was on Christmas Eve in 2015 when Peng went to Corey’s office to discuss a recent discovery: The nerve fibers in samples of herpes-infected skin were studded with receptors for IL-17c. They matched like a lock and key. That observation, in concert with the finding that the virus was linked to nerve growth, made it obvious that IL-17c was binding to the receptors on the tips of nerve fibers, and turning on growth like a switch.

“I could see his eyes just totally light up,” said Peng.

During 2016, a succession of detailed experiments provided convincing confirmation that IL-17c was indeed promoting the growth of sensory nerves. The protein also appears to protect nerve fibers from damage, tamping down a natural process of cellular suicide that can occur when nerve tissues are under stress.

The Fred Hutch finding is novel, and the next step will be to see if IL-17c can be formulated into some kind of topical cream or injectable medicine to repair nerves damaged by chemotherapy. There is a long and uncertain road from a laboratory discovery to a successful drug. The effects of this protein in reducing chemotherapy related peripheral neuropathy have yet to be tested in animals, let alone humans.

Peripheral neuropathy can be caused by cancer treatments that damage nerves adjacent to skin. Patients experience symptoms that range from stabbing pain to dangerous numbness in hands and feet. About two of every three patients that are given the most common chemotherapy drugs experience peripheral neuropathy following treatment. Peripheral nerves can rebound, but after six months, symptoms of numbness, tingling or pain are still experienced by 30 percent of patients. The effects can be permanent. Treatment options for peripheral neuropathy are limited.

Corey, who is also president and director emeritus of Fred Hutch, said Nerve Growth Factor, the first neurotrophin to be identified — earning its discoverers a Nobel Prize in 1986 — had been tried against neuropathy, but it actually caused an increase in pain. Another neurotrophin, called BDNF, triggers sensory nerve growth, but its biological activity is short-lived.

The intrinsic appeal of IL-17c is that it functions naturally in the environment where sensation occurs — at the junction of skin cells and nerve fibers. And its connection with herpes simplex is intriguing: in contrast to other related viruses such as varicella-zoster, which causes chickenpox and shingles, HSV leaves no evidence of nerve loss.

“Herpes simplex is a recurrent infection,” said Zhu. “Once a person has it, the virus never leaves them. Periodic recurrences happen all the time, but the patient never really loses sensation.”

Corey pointed out that varicella-zoster does not appear to cause skin cells to produce IL-17c, and reactivations of that virus cause painful nerve damage. HSV-1 and HSV-2, on the other hand, do induce production of the protein, and reactivation of these viruses yields no loss of sensation or neuropathy.

In addition to Fred Hutch, the 14 co-authors of the study are from the Department of Laboratory Medicine, the Department of Medicine and the Laboratory of Developmental Biology at the University of Washington and the Department of Microbiology and Immunology at Harvard Medical School.

The National Institutes of Health and the James B. Pendleton Charitable Trust supported this study.

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