A new study led by Dartmouth researchers, in collaboration with Harvard Medical School, suggests that even minimal exposure to the herpes simplex virus (HSV) in infant mice can lead to cognitive decline later in life. Published in PLoS Pathogens, this groundbreaking research highlights potential long-term neurological consequences of HSV exposure during infancy, shedding light on emerging connections between HSV and Alzheimer’s disease in humans.
HSV infections are widespread and often affect the skin and nervous system. While these infections are typically dormant and do not cause severe health issues in adults, they can be much more dangerous for newborns with underdeveloped immune systems. Neonatal HSV infections, which affect around 14,000 newborns globally each year, can cause severe disease and even death. However, what has been less understood is the potential for long-term neurological damage following asymptomatic neonatal HSV infections—those where there are no obvious symptoms at the time.
David Leib, PhD, a professor of Microbiology and Immunology at Dartmouth’s Geisel School of Medicine, explained, “Clinical outcomes of neonatal HSV infections, where symptoms have been readily apparent, have been well-studied. But little has been known about the frequency of, or outcomes following, asymptomatic neonatal HSV and how it may contribute to long-term neurological damage.”
To investigate the long-term effects of asymptomatic neonatal HSV infections, the research team developed a novel low-dose intranasal HSV infection model. They introduced the virus to one-day-old mouse pups, waited six months for the mice to mature, and then tested their cognitive and memory abilities. These tests were designed to mirror those used to track Alzheimer’s disease progression in humans.
The results were striking. The study found that mice who had received a very small dose of HSV as newborns exhibited noticeable cognitive decline. These mice performed worse in learning and memory tests compared to uninfected control mice, demonstrating that even a minor, asymptomatic infection early in life could have a lasting impact on cognitive function.
Abigail Dutton and Evelyn Turnbaugh, PhD candidates at Dartmouth and first-and-second authors of the study, stated that the results “reinforce the idea that low-level infections in neonates can have major consequences later in life despite causing little to no symptoms at the time of infection—a slightly scary concept.”
On a hopeful note, the researchers found that maternal vaccination in mice could prevent this cognitive decline. When mothers were vaccinated against HSV, their pups were protected from the virus and its associated memory loss. This protection was provided through the antibodies passed from mother to offspring either in utero or through breastfeeding during the first days of life.
David Leib noted, “Maternal vaccination for other infections in humans is already effective, and new maternal vaccines are being developed and tested in clinical trials. This could provide a viable approach to preventing cognitive impairment caused by neonatal HSV infection.”
The research team also plans to explore pharmacological treatments to mitigate the cognitive decline associated with neonatal HSV infections. This could include testing antiviral drugs to stop the virus from reactivating in the brain or anti-inflammatory drugs to prevent immune-mediated damage to brain cells.
Leib and his colleagues are hopeful that these investigations will yield further insights into how viral infections early in life could lead to neurological impairments and whether these effects can be counteracted through medical intervention.
Leib believes that the study’s findings could have profound implications for understanding human neurodegenerative diseases, such as Alzheimer’s disease. “Our findings may help to model the processes involved in diseases like Alzheimer’s, where abnormal immune responses and viral reactivation are thought to play a role in disease progression,” he said. “The idea that neonatal HSV infections could contribute to Alzheimer’s-like cognitive decline later in life opens up new avenues for research and potential therapeutic approaches.”
This study is a crucial step forward in understanding the long-term consequences of neonatal HSV infections, particularly those that are asymptomatic. The discovery that even low-level viral exposure can lead to cognitive decline later in life raises important questions about the role of viral infections in neurodegenerative diseases. Additionally, the success of maternal vaccination in protecting against this decline suggests a potential avenue for reducing the risk of long-term neurological damage in human populations, particularly for newborns exposed to HSV.
As the research continues, Leib and his team are committed to investigating further treatments, including antivirals and anti-inflammatory therapies, that could help prevent or mitigate the damage caused by such infections, paving the way for more effective strategies to combat memory loss and cognitive impairments later in life.
