Antiviral therapy · 2013
Inhibition of myosin light chain kinase can be targeted for the development of new therapies against herpes simplex virus type-1 infection.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Antoine Thessicar E, Shukla Deepak
Аннотация
BACKGROUND: Herpes simplex virus type-1 (HSV-1) is the leading cause of infectious blindness worldwide. Through a multistep process, HSV-1 enters into naturally susceptible human corneal epithelial (HCE) cells where it establishes an optimal environment for viral replication and spread. HSV-1 employment of cytoskeletal proteins, kinases, and cell signalling pathways is crucial for the entry process.
METHODS: Here we demonstrate that non-muscle myosin IIA (NM-IIA) and/or a myosin activating kinase, myosin light chain kinase (MLCK), can be targeted for the development of new and effective therapies against HSV-1. HCE cells were incubated with MLCK inhibitors ML-7 and ML-9 and NM-IIA inhibitor blebbistatin. Following the application of inhibitors, HSV-1 entry and spread to neighbouring HCE cells was evaluated.
RESULTS: Upon application of MLCK inhibitors ML-7 and ML-9 and NM-IIA inhibitor blebbistatin, HSV-1 entry into HCE cells was significantly decreased. Furthermore, dramatic impairment of glycoprotein-mediated membrane fusion was seen in cells treated with MLCK inhibitors, thus establishing a role for MLCK activation in cell-to-cell fusion and multinucleated syncytial cell formation. These results also indicate that the activation of motor protein NM-IIA by MLCK is crucial for cytoskeletal changes required for HSV-1 infection of corneal cells.
CONCLUSIONS: We provide new evidence that NM-IIA and MLCK can be used as effective antiviral targets against ocular herpes.
METHODS: Here we demonstrate that non-muscle myosin IIA (NM-IIA) and/or a myosin activating kinase, myosin light chain kinase (MLCK), can be targeted for the development of new and effective therapies against HSV-1. HCE cells were incubated with MLCK inhibitors ML-7 and ML-9 and NM-IIA inhibitor blebbistatin. Following the application of inhibitors, HSV-1 entry and spread to neighbouring HCE cells was evaluated.
RESULTS: Upon application of MLCK inhibitors ML-7 and ML-9 and NM-IIA inhibitor blebbistatin, HSV-1 entry into HCE cells was significantly decreased. Furthermore, dramatic impairment of glycoprotein-mediated membrane fusion was seen in cells treated with MLCK inhibitors, thus establishing a role for MLCK activation in cell-to-cell fusion and multinucleated syncytial cell formation. These results also indicate that the activation of motor protein NM-IIA by MLCK is crucial for cytoskeletal changes required for HSV-1 infection of corneal cells.
CONCLUSIONS: We provide new evidence that NM-IIA and MLCK can be used as effective antiviral targets against ocular herpes.