A study led by CU Anschutz and funded by the National Institutes of Health (NIH) is examining the link between two common viruses and dementia and other brain disorders.
For years, scientists believed that preventing the painful skin manifestations was the end game of varicella-zoster virus (VZV) vaccinations – the virus that causes chickenpox and shingles. But new evidence has emerged that demonstrates how targeting the downstream effects of the virus may help improve long-term health.
“Vaccines protect against the rash, but we believe the rash is just the tip of the iceberg,” said Andrew Bubak, PhD, associate professor of neurology at CU Anschutz School of Medicine.
The takeaway:
Researchers at CU Anschutz have received NIH funding to study how the viruses that cause shingles and cold sores may work together to increase the risk of stroke, dementia and chronic pain. The findings could lead to new therapies to prevent these complications.
Bubak’s research suggests that VZV uses exosomes – tiny particles that cells release to communicate – to carry a viral protein that suppresses immune defenses. The researchers believe this occurs even when the viruses are not causing symptoms such as rash.
Another common virus, herpes simplex virus type 1 (HSV-1), which causes cold sores and fever blisters, may worsen the effects of VZV when the viruses are reactivated at the same time.
Christy Niemeyer, PhD, assistant professor of neurology at CU Anschutz, studies HSV-1. She and Bubak recently published a review that highlights growing evidence that rather than acting independently, the viruses reactivate at the same time more frequently than previously thought, especially in older adults and people with weakened immune systems, causing damage in the brain.
“We believe VZV is setting the stage, but HSV-1 is the virus that’s coming into the brain and doing damage,” Niemeyer said.
Most people carry VZV, with some estimates suggesting that up to 95% of the world's population has the virus. Even people born after 1995, when the chickenpox vaccine was introduced, carry VZV because the vaccine uses a weakened live form of the virus to protect against chickenpox.
VZV remains dormant in nerve cells and later in life can reactivate as shingles, often during periods of extreme stress, immunosuppression, injury or natural aging. In addition to traveling to the skin, on reactivation the virus can travel to any organ or tissue (including blood vessels in the brain) to cause disease. And while vaccines such as Shingrix prevent shingles blisters on the skin, Bubak said the virus is still active in the body – and capable of causing problems.
Shingles is known for causing severe, lingering pain that can persist for months or even years. But its complications extend beyond pain. After a shingles infection, the risk of stroke remains elevated for up to a year, with the highest risk among people who develop a shingles rash on their face. Research also suggests that reactivation of VZV may increase the risk of dementia. Adults younger than 50 who develop shingles face an even greater risk of stroke – and shingles cases in this age group are becoming increasingly common for reasons not yet understood.
“My whole crusade is to get the word out that VZV is much more than a skin disease-causing virus,” Bubak said. “It’s not a disease of the elderly, either.”
Definitions:
Exosomes: Exosomes are tiny membrane-bound particles that are released by cells, carrying proteins, genetic material and other molecules to communicate with neighboring cells.
Reactivation: Reactivation occurs when a virus that has remained dormant in the body becomes active again.
Dormant virus: A dormant virus remains inactive inside the body without causing symptoms until it is triggered to reactivate.
Exosomes, or extracellular vesicles, are essential to cell communication. They are membrane-bound particles that contain micro-RNAs, proteins, enzymes and more, and they are released from every cell. These “little envelopes” carry information – and viruses such as VZV and HSV-1 have “hijacked” that system.
“We were the first lab to show how VZV uses these exosomes,” Bubak said. “They don’t contain the infectious virus, because VZV is cell-associated, but they do contain a single viral protein. The protein gets packaged into the exosomes.”
These exosomes get “taken up” by other cells, and the viral protein shuts down the defenses of the receiving cell.
“It’s a true Trojan horse,” Bubak said. “The protein itself isn’t infectious, but it shuts everything down. Then the infectious virus can enter and infect the cell.”
This is an important – and previously undescribed — mechanism of VZV, Bubak said.
There is currently no vaccine for HSV-1. Shingrix, the current shingles vaccine, targets a VZV protein called glycoprotein E. While this protein is important for preventing skin rash and the reason Shingrix is so effective, the hope is that the new target would block the immune suppression that leads to increased risk of stroke and dementia.
Most adults also have HSV-1, with estimates ranging from 60-90% of adults worldwide, Niemeyer says. Evidence has already shown that when HSV-1 and VZV are reactivated together, outcomes are worse.
Individually, HSV-1 and VZV increase dementia risk when reactivated. If they reactivate together, the risk appears to be even higher.
“Most of the time when we study viruses, we study one at a time. But viruses like VZV and HSV-1 don’t exist in a vacuum. And in the real world, most people have both of these viruses dormant inside of them, and so little is known about their interactions and how they may be both contributing in shared ways to our overall immune and brain health,” Niemeyer said.
In the lab, Bubak and Niemeyer looked at exosomes.
“We ran experimental studies in animals. Sure enough, delivering VZV exosomes containing that one protein shut down the immune defenses. Then when we introduced HSV-1, the virus went straight to the brain in all of our animals,” Bubak said.
In their new study, Bubak and Niemeyer will block the specific VZV protein to see if they can stop HSV-1 from entering the brain.
“By not studying these viruses in silos and thinking about real world conditions people are experiencing, we can look more holistically at what’s happening clinically which can potentially help us develop new therapies,” Niemeyer said.
Key points:
NIH-funded CU Anschutz researchers are studying VZV and HSV-1 reactivation and how the viruses work together to cause harm to the brain.
VZV may weaken immune defenses using exosomes, and HSV-1 may exploit this weakness to enter the brain.
Understanding this interaction could lead to a better scientific understanding of how these viruses interact, which may lead to new targeted therapies to improve brain health and prevent stroke, dementia and chronic pain.
Researchers hope to move beyond preventing shingles rash toward preventing long-term neurological disease.
Photo at top: Andrew Bubak, PhD, peers at viruses in his CU Anschutz lab.