Very early exposure to even a very small dose of herpes simplex virus (HSV) in infant mice can lead to cognitive decline later in life, according to findings from a new Dartmouth-led study, in collaboration with Harvard Medical School and published in the journal PLoS Pathogens. This is significant because of emerging data in human studies showing an association between HSV and Alzheimer’s disease in humans.
HSV infections are very common, typically affecting the skin and the nervous system. While these infections often lay dormant in the body and usually don’t pose serious health risks, HSV can be much more dangerous for those with underdeveloped immune systems such as newborns. Neonatal HSV, which is associated with high rates of disease and death, affects about 14,000 newborns worldwide each year.
“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,” explains David Leib, PhD, chair and professor of Microbiology and Immunology at Dartmouth’s Geisel School of Medicine, who served as a corresponding author on the study in a collaboration with Katherine Nautiyal, PhD, assistant professor of Psychological and Brain Sciences at Dartmouth. The research project was led by first-and-second authors Abigail Dutton and Evelyn Turnbaugh, MD/PhD and PhD candidates, respectively, at Geisel and the Guarini School of Graduate and Advanced Studies at Dartmouth.
Neurological impacts from neonatal HSV infections
To assess potential neurological outcomes associated with asymptomatic neonatal HSV infections, with no overt signs of infection present, the research team developed a very low-dose intranasal HSV infection model. They introduced the virus to one-day-old mouse pups, waited six months for them to mature, and then ran them through a range of cognitive and memory tests, some which are derived from tests given to patients with Alzheimer’s disease to track disease progression.
“What Abby and Evelyn discovered was that mice who had received a miniscule dose of HSV when they were a day old, weren’t able to learn as well as those that were in the control group and were uninfected. This reinforces 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,” says Leib.
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On a more positive note, the team, building on work previously done at Dartmouth, was able to show that maternal vaccination (in mice) can prevent this cognitive decline. “When the moms were vaccinated against HSV, their pups were protected from viral infection and memory loss by antibodies that they received from moms in utero or through their milk during their first days of life,” he explains, noting that maternal vaccination for other infections in humans is effective and that new maternal vaccines are being developed and tested in clinical trials.
Reduction in neonatal cognitive impairment
Next, Leib and his colleagues plan to test the effectiveness of some pharmacological approaches to combat the virus. “We’ll be asking, ‘Are there ways to actually ameliorate the cognitive decline?’, either with antiviral drugs to stop virus reactivation or perhaps anti-inflammatory drugs to prevent immune-mediated damage—we’ll be looking to get at the mechanism of how the damage occurs.
“In any case, I think the outstanding work done by Abby, Evelyn, and our team in this study shows that maternal vaccination could be an effective strategy for reducing neurological impairment in infected offspring, and that our findings may have profound implications for understanding and modeling human neurogenerative disorders such as Alzheimer’s disease,” says Leib.
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