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Deepak Shukla, Thessicar Antoine, Vaibhav Tiwari; Defining a new role for cytoskeletal alterations in corneal herpetic disease. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6263.
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Herpes simplex virus type-1 (HSV-1) is the leading cause of infectious blindness worldwide. Perturbation of cytoskeleton by the virus can exacerbate the disease symptoms. Here we investigate the viral hijacking of cytoskeleton components such as non-muscle myosins and myosin light chain kinases in the establishment of a productive HSV-1 infection of the cornea.
Protein knockdown was performed by RNA interference. HSV-1 infection of human corneal epithelial cells and cultured corneas was analyzed by reporter virus assay, viral protein translocation assay, and immunofluorescence. Inhibitors of cytoskeleton proteins were used. Virus spread was analyzed by fluorescence measurement and confocal microscopy. Cytoskeletal changes were identified via F-actin staining and confocal microscopy. A microarray analysis was performed to determine changes in pro-inflammatory cytokines. Effects of soluble glycoproteins and viral protein over-expression were analyzed.
Here we demonstrate that non muscle myosin II and VI, a myosin activating kinase, myosin light chain kinase (MLCK) are controlled by the virus for the remodeling of host cytoskeleton and the transport of viral capsids. Knockdown of cytoskeletal proteins and inhibitors of MLCK can result in the loss of productive viral infection. Targeting the host components can also reduce viral spread, show strong therapeutic effects and define a possible new treatment of symptoms originating from ocular herpes. Damage to the cytoskeleton may be a reason for the development of stromal herpetic keratitis
Our results demonstrate that perturbation of cytoskeleton in the cells of the corneal epithelium is a direct consequence of herpetic infection and it is triggered by viral glycoproteins gD and gB. Involvement of actomyosin components is required and is controlled by the virion proteins. Virus-induced cytoskeletal changes may contribute to the induction of pro-inflammatory cytokines.
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