The US11 Gene of Herpes Simplex Virus 1 Promotes Neuroinvasion and Periocular Replication following Corneal Infection

Abstract

Herpes simplex virus 1 (HSV-1) cycles between phases of latency in sensory neurons and replication in mucosal sites. HSV-1 encodes two key proteins that antagonize the shutdown of host translation, US11 through preventing PKR activation and ICP34.5 through mediating dephosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α). While profound attenuation of ICP34.5 deletion mutants has been repeatedly demonstrated, a role for US11 in HSV-1 pathogenesis remains unclear. We therefore generated an HSV-1 strain 17 US11-null virus and examined its properties in vitro and in vivo. In U373 glioblastoma cells, US11 cooperated with ICP34.5 to prevent eIF2α phosphorylation late in infection. However, the effect was muted in human corneal epithelial cells (HCLEs), which did not accumulate phosphorylated eIF2α unless both US11 and ICP34.5 were absent. Low levels of phosphorylated eIF2α correlated with continued protein synthesis and with the ability of virus lacking US11 to overcome antiviral immunity in HCLE and U373 cells. Neurovirulence following intracerebral inoculation of mice was not affected by the deletion of US11. In contrast, the time to endpoint criteria following corneal infection was greater for the US11-null virus than for the wild-type virus. Replication in trigeminal ganglia and periocular tissue was promoted by US11, as was periocular disease. The establishment of latency and the frequency of virus reactivation from trigeminal ganglia were unaffected by US11 deletion, although emergence of the US11-null virus occurred with slowed kinetics. Considered together, the data indicate that US11 facilitates the countering of antiviral response of infected cells and promotes the efficient emergence of virus following reactivation. IMPORTANCE Alphaherpesviruses are ubiquitous DNA viruses and include the human pathogens herpes simplex virus 1 (HSV-1) and HSV-2 and are significant causes of ulcerative mucosal sores, infectious blindness, encephalitis, and devastating neonatal disease. Successful primary infection and persistent coexistence with host immune defenses are dependent on the ability of these viruses to counter the antiviral response. HSV-1 and HSV-2 and other primate viruses within the Simplexvirus genus encode US11, an immune antagonist that promotes virus production by preventing shutdown of protein translation. Here we investigated the impact of US11 deletion on HSV-1 growth in vitro and pathogenesis in vivo. This work supports a role for US11 in pathogenesis and emergence from latency, elucidating immunomodulation by this medically important cohort of viruses.

Herpes simplex keratitis: A brief clinical overview

“…Recurrence of HSV infection is widely agreed to be the result of virus reactivation in the trigeminal nerve ganglion; which travels along nerve axons to introduce its genome into the eye and initiate replication using the eye’s cellular processes to make new copies of the virus. US-11 protein encoded in HSV-1 may play a role in the pathogenesis of worsening keratitis by promoting the translation of viral amino acids following the reactivation of HSV[ 80 ]. There is evidence supporting the presence of latent virus in cornea tissue, this could be the cause of recurrent donor-derived HSV, however, this is still very controversial[ 81 ].…”

Gaudichaudione H inhibits Herpes Simplex Virus-1 replication by regulating cellular nuclear factor-κB in an interferon-γ-inde-pendent manner

“…ICP34.5 is implicated in many aspects of viral pathogenesis. It is targeted by host IFN responses to impede protein synthesis by counteracting PKR activity and reversing EIF2α phosphorylation [22]. We used a stable ICP34.5 knockout KOS virus called KOS34.5.…”

Targeting the integrated stress response in ophthalmology

“…24 The ability of countering antiviral response of infected cells promotes HSV-1 neuroinvasion and periocular replication following corneal infection. 82 ER stress was also known to involve in the pathogenesis of chronic inflammatory and autoimmune diseases, including dry eye. Pflugfelder's group has demonstrated interferon-γ (IFN-γ) could induce unfolded protein response and the expression of ATF4, and thus resulted decreased mucin synthesis and reduced goblet cell proliferation in the cultivated conjunctival goblet cell harvested from C57BL mice.…”