Newborns are significantly more susceptible to severe
viral encephalitis than adults, with differences in the host response to
infection implicated as a major factor. However, the specific host signaling pathways responsible for differences in susceptibility and neurologic morbidity have remained unknown. In a murine model of HSV
encephalitis, we demonstrated that the choroid plexus (CP) is susceptible to herpes simplex virus 1 (HSV-1) early in
infection of the newborn but not the adult brain. We confirmed susceptibility of the CP to HSV
infection in a human case of newborn HSV
encephalitis. We investigated components of the
type I interferon (IFN) response in the murine brain that might account for differences in cell susceptibility and found that newborns have a dampened
interferon response and significantly lower basal levels of the alpha/
beta interferon (IFN-α/β) receptor (IFNAR) than do adults. To test the contribution of IFNAR to restricting
infection from the CP, we infected IFNAR knockout (KO) adult mice, which showed restored CP susceptibility to HSV-1
infection in the adult. Furthermore, reduced IFNAR levels did not account for differences we found in the basal levels of several other innate signaling
proteins in the wild-type newborn and the adult, including
protein kinase R (PKR), that suggested specific regulation of innate immunity in the developing brain. Viral targeting of the CP, a region of the brain that plays a critical role in neurodevelopment, provides a link between newborn susceptibility to HSV and long-term neurologic morbidity among survivors of newborn HSV
encephalitis.
IMPORTANCE: Compared to adults, newborns are significantly more susceptible to severe disease following HSV
infection. Over half of newborn HSV
infections result in disseminated disease or
encephalitis, with long-term neurologic morbidity in 2/3 of
encephalitis survivors. We investigated differences in host cell susceptibility between newborns and adults that contribute to severe
central nervous system disease in the newborn. We found that, unlike the adult brain, the newborn choroid plexus (CP) was susceptible early in HSV-1
infection. We demonstrated that IFN-α/β receptor levels are lower in the newborn brain than in the adult brain and that deletion of this receptor restores susceptibility of the CP in the adult brain. The CP serves as a barrier between the blood and the cerebrospinal fluid and plays a role in proper neurodevelopment. Susceptibility of the newborn choroid plexus to HSV-1 has important implications in viral spread to the brain and, also, in the neurologic morbidity following HSV
encephalitis.