Asymptomatic neonatal herpes simplex virus infection in mice leads to persistent CNS infection and long-term cognitive impairment

Neonatal herpes simplex virus (nHSV) is a devastating infection impacting approximately 14,000 newborns globally each year. nHSV infection is associated with high neurologic morbidity and mortality, making early intervention critical. Clinical outcomes of symptomatic nHSV infections are well-studied, but little is known about the frequency of, or outcomes following, subclinical or asymptomatic nHSV. Given the ubiquitous nature of HSV infection and frequency of asymptomatic shedding in adults, subclinical infections are underreported and could contribute to long-term neurological damage. To assess potential neurological morbidity associated with subclinical nHSV infection, we developed a low-dose (100 PFU) intranasal HSV infection model in neonatal wild-type C57BL/6 mice. At this dose, HSV DNA was detected in the brain by quantitative PCR (qPCR) but was not associated with acute clinical signs of infection. However, months after neonatal inoculation with this low dose of HSV, we observed impaired mouse performance on a range of cognitive and memory tests. Memory impairment was induced by infection with either HSV-1 or HSV-2 wild-type viruses, indicating that the cognitive impairment associated with neonatal infection was not strain-specific. Maternal immunization reduced neonate central nervous system (CNS) viral burden and prevented offspring from developing neurological sequelae following nHSV infection. Altogether, these results support the idea that subclinical neonatal infections may lead to cognitive decline in adulthood and that maternal vaccination is an effective strategy for reducing neurological sequelae in infected offspring. These findings may have profound implications for understanding and modeling the etiology of human neurodegenerative disorders such as Alzheimer's Disease.