HSV targeting of the host phosphatase PP1α is required for disseminated disease in the neonate and contributes to pathogenesis in the brain

Douglas R. Wilcox, William J. Muller, Richard Longnecker*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Newborns are significantly more susceptible to severe disease after infection with herpes simplex virus (HSV) compared with adults, with differences in the host response implicated as a major factor. To understand host response differences between these age groups, we investigated the shutoff of protein synthesis by the host and the retargeting of host phosphatase PP1α by the HSV-1 protein γ34.5 for reversal of translational arrest. In a murine newborn model of viral dissemination, infection with the HSV-1 mutant for PP1α binding resulted in complete absence of disease. PP1α-binding mutant HSV-1 replicated in visceral organs early after inoculation, demonstrating that HSV-1 replication requires PP1α-targeting only later in infection. Newborn mice deficient in type I IFN signaling partially rescued the virulence of the PP1α-binding mutant virus, suggesting an IFN-independent role for eIF2α kinases during infection. When we investigated the contribution of PP1α targeting to pathogenesis in the brain, we found that the inability of HSV-1 to bind PP1α increased survival time in both newborn and adult mice. Unlike disseminated disease, type I IFN signaling in the brain was required to attenuate disease following PP1α-mutant virus infection. Furthermore, pharmacologic inhibition of eIF2α dephosphorylation reduced HSV-1 replication in a brain slice culture model of encephalitis. Our findings reveal agedependent differences in γ34.5 function and tissue-specific reliance on the type I IFN response for protection from HSV disease. These results define an important role for γ34.5 in neonatal infections in contrast to other studies indicating that the autophagyinhibiting function of γ34.5 is dispensable for pathogenesis in the newborn brain.

Original languageEnglish (US)
Article numberE6937
Pages (from-to)E6937-E6944
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number50
StatePublished - Dec 15 2015


  • Disseminated disease
  • HSV-1
  • Interferon response
  • Translational arrest

ASJC Scopus subject areas

  • General


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