Herpes Simplex Virus 1 Replication, Ocular Disease, and Reactivations from Latency Are Restricted Unilaterally after Inoculation of Virus into the Lip

Abstract

Ocular herpes simplex keratitis (HSK) is a consequence of viral reactivations from trigeminal ganglia (TG) and occurs almost exclusively in the same eye in humans. In our murine oro-ocular (OO) model, herpes simplex virus 1 (HSV-1) inoculation in one side of the lip propagates virus to infect the ipsilateral TG. Replication here allows infection of the brainstem and infection of the contralateral TG. Interestingly, HSK was observed in our OO model only from the eye ipsilateral to the site of lip infection. Thus, unilateral restriction of HSV-1 may be due to differential kinetics of virus arrival in the ipsilateral versus contralateral TG. We inoculated mice with HSV-1 reporter viruses and then superinfected them to monitor changes in acute- and latent-phase gene expression in TG after superinfection compared to the control (single inoculation). Delaying superinfection by 4 days after initial right lip inoculation elicited failed superinfecting-virus gene expression and eliminated clinical signs of disease. Initial inoculation with thymidine kinase-deficient HSV-1 (TKdel) completely abolished reactivation of wild-type (WT) superinfecting virus from TG during the latent stage. In light of these seemingly failed infections, viral genome was detected in both TG. Our data demonstrate that inoculation of HSV-1 in the lip propagates virus to both TG, but with delay in reaching the TG contralateral to the side of lip infection. This delay is responsible for restricting viral replication to the ipsilateral TG, which abrogates ocular disease and viral reactivations from the contralateral side. These observations may help to understand why HSK is observed unilaterally in humans, and they provide insight into vaccine strategies to protect against HSK. IMPORTANCE Herpetic keratitis (HK) is the leading cause of blindness by an infectious agent in the developed world. This disease can occur after reactivation of herpes simplex virus 1 in the trigeminal ganglia, leading to dissemination of virus to, and infection of, the cornea. A clinical paradox is evidenced by the bilateral presence of latent viral genomes in both trigeminal ganglia, while for any given patient the disease is unilateral with recurrences in a single eye. Our study links the kinetics of early infection to unilateral disease phenomenon and demonstrates protection against viral reactivation when kinetics are exploited. Our results have direct implications in the understanding of human disease pathogenesis and immunotherapeutic strategies for the treatment of HK and viral reactivations.

Akių Herpetinės Infekcijos Ir Jų Gydymas

“…Išskiriama pirminė ir pasikartojanti akių herpetinė infekcija. Pirminę infekciją dažniausiai sukelia tiesioginis viruso patekimas ant akies paviršiaus, arba ji kyla iš herpesvirusinės infekcijos burnos ir veido srityje, virusui retrogradiškai keliaujant trišakio nervo šaka -akiniu nervu [13]. Imunosupresyviems asmenims pirminę infekciją gali sukelti autoinokuliacija iš aktyvios herpetinės infekcijos židinių kitose organizmo vietose.…”

“…Dominuojanti infekcijos sritis yra burnos ir veido regionas, kurios yra inervuojamos trišakio nervo šaka -viršutinio žandikaulio nervu. Virusas šia šaka keliauja į trišakio nervo mazgą, kurio neuronuose būna latentinės būsenos [13]. Tam tikri stimulai, pavyzdžiui, trauma, ultravioletinė spinduliuotė, imunosupresija, stresas, hormoniniai pokyčiai (menstruacijos) skatina viruso perėjimą į aktyvią būseną.…”

Advancing Our Understanding of Corneal Herpes Simplex Virus-1 Immune Evasion Mechanisms and Future Therapeutics

“…From here, the nucleocapsid can translocate to the trigeminal ganglia, where the virus can establish latency. If reactivation of the virus is triggered by any of the common factors responsible for reactivation, an ocular infection can occur, even if the original viral route of entry was not the eyes [ 56 ].…”

E3 ligase RNF5 inhibits type I interferon response in herpes simplex virus keratitis through the STING/IRF3 signaling pathway

“…After the initial stage, HSV-1 enters the trigeminal ganglion through the corneal nerve and can continue to replicate in the trigeminal ganglion or enter a latent state. Under the influence of stress, fever, ultraviolet radiation, weakened immunity, and other factors, the virus is reactivated, leading to recurrent infections ( Poccardi et al, 2019 ). Although HSV corneal epithelitis resolves spontaneously within a week, without proper treatment, it could trigger the development of HSK and immune-mediated infiltration of the stroma, resulting in progressive corneal opacity and neovascularization that directly affects vision ( Lobo et al, 2019 ).…”