Newborns are more susceptible to severe disease from
infection than adults, with maturation of immune responses implicated as a major factor. The
type I interferon response delays mortality and limits viral replication in adult mice in a model of herpes simplex virus (HSV)
encephalitis. We found that intact
type I interferon signaling did not control HSV disease in the neonatal brain. However, the multifunctional HSV
protein γ34.5 involved in countering
type I interferon responses was important for virulence in the brain in both age groups. To investigate this observation further, we studied a specific function of γ34.5 which contributes to HSV pathogenesis in the adult brain, inhibition of the cellular process of autophagy. Surprisingly, we found that the beclin binding domain of γ34.5 responsible for inhibiting autophagy was dispensable for HSV disease in the neonatal brain, as
infection of newborns with the deletion mutant decreased time to mortality compared to the rescue virus. Additionally, a functional beclin binding domain in HSV γ34.5 did not effectively inhibit autophagy in the neonate, unlike in the adult. Type I IFN responses promote autophagy in adult, a finding we confirmed in the adult brain after HSV
infection; however, in the newborn brain we observed that autophagy was activated through a type I IFN-independent mechanism. Furthermore, autophagy in the wild-type neonatal mouse was associated with increased apoptosis in infected regions of the brain. Observations in the mouse model were consistent with those in a human case of neonatal HSV
encephalitis. Our findings reveal age-dependent differences in autophagy for protection from HSV
encephalitis, indicating developmental differences in induction and regulation of this innate defense mechanism after HSV
infection in the neonatal brain.