| First Author | Wilcox DR | Year | 2015 |
| Journal | Proc Natl Acad Sci U S A | Volume | 112 |
| Issue | 50 | Pages | E6937-44 |
| PubMed ID | 26621722 | Mgi Jnum | J:228201 |
| Mgi Id | MGI:5705663 | Doi | 10.1073/pnas.1513045112 |
| Citation | Wilcox DR, et al. (2015) HSV targeting of the host phosphatase PP1alpha is required for disseminated disease in the neonate and contributes to pathogenesis in the brain. Proc Natl Acad Sci U S A 112(50):E6937-44 |
| abstractText | 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 PP1alpha by the HSV-1 protein gamma34.5 for reversal of translational arrest. In a murine newborn model of viral dissemination, infection with the HSV-1 mutant for PP1alpha binding resulted in complete absence of disease. PP1alpha-binding mutant HSV-1 replicated in visceral organs early after inoculation, demonstrating that HSV-1 replication requires PP1alpha-targeting only later in infection. Newborn mice deficient in type I IFN signaling partially rescued the virulence of the PP1alpha-binding mutant virus, suggesting an IFN-independent role for eIF2alpha kinases during infection. When we investigated the contribution of PP1alpha targeting to pathogenesis in the brain, we found that the inability of HSV-1 to bind PP1alpha 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 PP1alpha-mutant virus infection. Furthermore, pharmacologic inhibition of eIF2alpha dephosphorylation reduced HSV-1 replication in a brain slice culture model of encephalitis. Our findings reveal age-dependent differences in gamma34.5 function and tissue-specific reliance on the type I IFN response for protection from HSV disease. These results define an important role for gamma34.5 in neonatal infections in contrast to other studies indicating that the autophagy-inhibiting function of gamma34.5 is dispensable for pathogenesis in the newborn brain. |
