A very common virus may do more than cause cold sores.
Researchers at the University of Colorado Anschutz have discovered how herpes simplex virus type 1 (HSV-1), the virus that causes cold sores, can fundamentally change how the brain’s immune cells respond to infection, revealing a potentially important connection between viral infection, chronic inflammation and Alzheimer’s Disease.
The findings, published in PLOS Pathogens, reveal that HSV-1 activates powerful antiviral defenses in the brain’s specialized immune cells, called microglia. But this response may come at a cost. As these cells shift towards fighting infection, they lose the ability to maintain a healthy brain.
“Microglia act as both the brain's security system and its maintenance crew,” said senior author Christy Niemeyer, PhD, assistant professor of neurology at CU Anschutz. “When HSV-1 enters the brain, these cells shift into emergency defense mode. While this helps fight the virus, it may also compromise their ability to perform the everyday functions, even after the virus is gone.”
HSV-1 infects more than 60% of people and remains in the body for life. Although serious complications are rare, growing evidence links HSV-1 to the chronic inflammation that may trigger Alzheimer’s disease. However, it is not clear how the virus may trigger and maintain this inflammation.
Using advanced molecular techniques, researchers examined how individual brain cells responded to HSV-1 infection and where these changes occurred.
They discovered that infection produced distinct populations of microglia dominated by interferon signaling, a powerful antiviral defense mechanism. At the same time, genes involved in the cells' normal protective and maintenance functions became less active.
Importantly, these changes were concentrated in brain regions where the virus was detected, suggesting that HSV-1 creates localized areas of heightened immune activity.
The researchers also found changes in chromatin, the material that packages DNA inside cells. These changes can affect how easily genes are turned on or off.
"What makes these findings particularly interesting is that the virus isn't simply triggering inflammation," Niemeyer said. "It's changing the molecular programs that control how these immune cells function. An important question is whether these changes persist after infection."
The findings provide a potential explanation for how viral infections could contribute to Alzheimer’s disease and other neurodegenerative disorders.
“Interestingly, the way that HSV-1 finely tunes the immune response in microglia, resemble patterns found in response to other factors that drive Alzheimer's disease,” said co-senior author Kimberley Bruce, PhD , associate professor of medicine at CU Anschutz. “Although we have not established that HSV-1 causes Alzheimer's, it highlights the immune programming of microglia as a common factor linking infection, aging and genetic risk factors.”
Niemeyer said Alzheimer's disease is influenced by multiple genetic and environmental factors.
"Understanding how a common virus changes the brain's immune environment may help us identify why some individuals become more vulnerable to neurodegeneration," she said.
The researchers next plan to investigate whether these immune changes persist after infection and how repeated viral reactivation may influence long-term brain health.
The other co-authors include: Seth Frietze, Cameron Lunn, Dean Oldham, Joseph R. Boyd, Andrew N. Bubak, Amalia Bustillos Saucedo, Maria A. Nagel, Diego Restrepo, Kimberley D. Bruce, Christy S. Niemeyer
Key Points
- The brain’s immune response shifts: HSV-1 activates antiviral defenses in microglia, the brain’s specialized immune cells, while reducing activity in genes responsible for maintaining brain health.
- Changes occur where the virus is detected: Researchers found distinct patterns of immune activity in brain regions with evidence of HSV-1 infection.
- The virus may alter how immune cells function: Infection was associated with changes in chromatin, which helps regulate whether genes are turned on or off.
- Implications for Alzheimer’s disease: The findings suggest that changes in microglia’s immune programming may be one link between viral infection, chronic inflammation and neurodegenerative disease. Researchers have not established that HSV-1 causes Alzheimer’s.
- Next steps: The team will investigate whether these immune changes persist after infection and how repeated viral reactivation may affect long-term brain health.