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

Abstract

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.erpes simplex virus (HSV) infections cause a wide spectrum of outcomes, ranging from asymptomatic acquisition to lethal dissemination and central nervous system (CNS) disease (1). Newborns are particularly susceptible to HSV disease with over 50% of infected newborns progressing to disseminated disease or encephalitis. Of those who survive the initial encephalitis, 2/3 of newborns will go on to have long-term neurologic morbidity (2). This is in contrast to the adult population, where occurrence of HSV encephalitis and disseminated disease are rare and infection with HSV is often subclinical (3). Either serotype of HSV (HSV-1 or HSV-2) may cause disease in newborns, but recent data suggest a rising incidence of HSV-1 genital infection, paralleled by a predominance of HSV-1 as a cause of newborn disease (4, 5). The striking difference in outcomes between adults and neonates infected with HSV suggests an age-dependent difference in susceptibility to disease based on host factors.It is likely that differences in the immune response in the neonate compared with the adult result in the disparate outcomes following HSV infection, and this was investigated in our current studies.One of the earliest responses to infection is the type I IFN response and the innate pathways modulated by the IFN-in...

Herpes Simplex Virus 1 γ 1 34.5 Protein Inhibits STING Activation That Restricts Viral Replication

“…To evade this, HSV-1 ␥ 1 34.5 recruits cellular phosphatase 1 (PP1), forming a high-molecular-weight complex that dephosphorylates eIF-2␣ (21)(22)(23). Accordingly, mutations in the PP1 binding site abrogate viral virulence (24,25). The ␥ 1 34.5 protein also inhibits autophagy, IFN induction, and dendritic cell maturation and facilitates glycoprotein processing as well as nuclear egress (6,(26)(27)(28)(29)(30)(31)(32)(33)(34).…”

The Type I Interferon Response and Age-Dependent Susceptibility to Herpes Simplex Virus Infection

“…. The IFNAR and PKR, two components previously shown to be important to control HSV infection in the brain (Leib et al, 2000;Wilcox et al, 2015a), were found to have 4-to 6-fold higher levels of basal expression in the adult, while other components such as STAT1, TBK1, cGAS, and TLR3 were present in lower levels in the adult brain. Interestingly, STING, another important component of the innate immune response to HSV in the brain (Parker et al, 2015), is present at similar levels in newborn and adult brains.…”

“…It also targets TLR signaling by promoting degradation of adaptor proteins MyD88 and Mal. The immediate early protein ICP27 targets the NF-kB and IRF-3 signaling pathways (Kim et al, 2008); g34.5, another major virulence factor, targets several pathways to counteract the host IFN response Roizman, 1992, 1994); g34.5 mediates the dephosphorylation of eIF2a and IKKa to reverse host shutoff of protein synthesis (He et al, 1997;Wilcox et al, 2015a), inhibits TBK1 to prevent activation of the type I IFN response (Verpooten et al, 2009), and binds to beclin-1 to inhibit autophagy (Orvedahl et al, 2007;Gobeil and Leib, 2012). The multiple strategies developed by the virus to neutralize the host type I IFN response strongly support the essential role of this pathway in controlling HSV infection .…”

Multifunctional viral protein γ34.5 manipulates nucleolar protein NOP53 for optimal viral replication of HSV-1

“…As indicated above, HSV-1 γ34.5 recruits phosphatase PP1α to reverse eIF2α-mediated translational arrest. It has been reported that PP1α contributes to HSV-1 pathogenesis and is required for disseminated disease in the brain 39 . To address whether NOP53 relates functionally with PP1α, okadaic acid (OA) was used to induce eIF2α phosphorylation in this study.…”