Abstract
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.
Highlights
Disease due to viral infection is a complex consequence of interactions between both viral and host factors
Newborns are susceptible to infectious illness compared to adults, and Herpes simplex virus (HSV) infection commonly results in devastating encephalitis
We studied the interaction of HSV with the type I interferon pathway and found that a specific activity of the viral protein c34.5, which counters host autophagy to promote encephalitis in adults, was not required to cause disease in newborns
Summary
Disease due to viral infection is a complex consequence of interactions between both viral and host factors. Herpes simplex virus (HSV) infections cause a wide spectrum of outcomes in humans, ranging from asymptomatic acquisition to lethal dissemination and encephalitis [1]. Newborns are susceptible to poor neurologic outcomes of central nervous system (CNS) disease from HSV [2]. Over half of neonatal HSV infections result in disseminated disease or encephalitis, with long-term neurologic morbidity in 2/3 of those who survive encephalitis. The disparate outcomes between HSV-infected neonates and adults suggest an age-dependent difference in susceptibility to disease based on host factors. Multiple layers of immunity are involved in the host response to HSV infection, and differences in immune responses of newborns compared with adults likely contribute to their increased susceptibility [7]. Multiple host signals important in immunity are targeted by the virus for modulation [8], and it is not clear how HSV may manipulate these responses differently in the newborn
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