Abstract
Herpes simplex virus-1 (HSV-1) causes lifelong infection affecting between 50 and 90% of the global population. In addition to causing dermal lesions, HSV-1 is a leading cause of blindness resulting from recurrent corneal infection. Corneal disease is characterized by loss of corneal immunologic privilege and extensive neovascularization driven by vascular endothelial growth factor-A (VEGF-A). In the current study, we identify HSV-1 infected cells as the dominant source of VEGF-A during acute infection, and VEGF-A transcription did not require TLR signaling or MAP kinase activation. Rather than being an innate response to the pathogen, VEGF-A transcription was directly activated by the HSV-1 encoded immediate early transcription factor, ICP4. ICP4 bound the proximal human VEGF-A promoter and was sufficient to promote transcription. Transcriptional activation also required cis GC-box elements common to the VEGF-A promoter and HSV-1 early genes. Our results suggest that the neovascularization characteristic of ocular HSV-1 disease is a direct result of HSV-1's major transcriptional regulator, ICP4, and similarities between the VEGF-A promoter and those of HSV-1 early genes.
Highlights
Herpes simplex virus-type 1 (HSV-1) is a neurotropic member of the alpha herpesvirus family with worldwide seroprevalence rates ranging from between 50–90%.[1,2]
We have previously discovered HSV-1 elicits corneal lymphangiogenesis through a unique mechanism involving vascular endothelial growth factor (VEGF)-A independent of that described for other insults including transplantation or bacterial infection
As vascular endothelial growth factor-A (VEGF-A) is involved in driving neovascularization associated with tumor growth and metastasis, proteins that influence transcriptional regulation of VEGF-A may be useful in the development of adjunct therapy for such disparate diseases as cancer and HSV-1 keratitis
Summary
Herpes simplex virus-type 1 (HSV-1) is a neurotropic member of the alpha herpesvirus family with worldwide seroprevalence rates ranging from between 50–90%.[1,2]. Virions gain access to sensory nerve fibers and are transported to neuronal cell bodies in the trigeminal ganglia where HSV-1 establishes a latent infection [3]. Infection is life-long as a result of the sequestration of latent virus from immunological surveillance [3]. Latency may be broken during times of stress or immunological suppression resulting in the resumption of the lytic viral replication cycle. Produced virions migrate down trigeminal nerve fibers to epithelial surfaces where the reactivated virus resumes lytic viral replication and infectious virions are released. Symptoms of reactivation may be as mild as dermal vesicles or as severe as herpes simplex encephalitis, the most common cause of sporadic viral encephalitis in the world [4]
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