Herpes simplex virus (HSV) infection induces a rapid and transient increase in intracellular calcium concentration ([Ca2+]i), which plays a critical role in facilitating viral entry. T-type calcium channel blockers and EGTA, a chelate of extracellular Ca2+, suppress HSV-2 infection. But the cellular mechanisms mediating HSV infection-activated Ca2+ signaling have not been completely defined. In this study we investigated whether the TRPV4 channel was involved in HSV-2 infection in human vaginal epithelial cells. We showed that the TRPV4 channel was expressed in human vaginal epithelial cells (VK2/E6E7). Using distinct pharmacological tools, we demonstrated that activation of the TRPV4 channel induced Ca2+ influx, and the TRPV4 channel worked as a Ca2+-permeable channel in VK2/E6E7 cells. We detected a direct interaction between the TRPV4 channel protein and HSV-2 glycoprotein D in the plasma membrane of VK2/E6E7 cells and the vaginal tissues of HSV-2–infected mice as well as in phallic biopsies from genital herpes patients. Pretreatment with specific TRPV4 channel inhibitors, GSK2193874 (1−4 μM) and HC067047 (100 nM), or gene silence of the TRPV4 channel not only suppressed HSV-2 infectivity but also reduced HSV-2-induced cytokine and chemokine generation in VK2/E6E7 cells by blocking Ca2+ influx through TRPV4 channel. These results reveal that the TRPV4 channel works as a Ca2+-permeable channel to facilitate HSV-2 infection in host epithelial cells and suggest that the design and development of novel TRPV4 channel inhibitors may help to treat HSV-2 infections.
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The research was supported by the National Natural Science Foundation of China (82003815 to PJ), Major Scientific and Technological Projects of Guangdong Province (2019B020202002 to SWL), Natural Science Foundation of Guangdong Province (2017A030310602 to PJ), Chinese Academy of Traditional Chinese Medicine (ZZ13-035-02 and 2019XZZX-LG04 to SWL), and Medical Scientific Research Foundation of Guangdong Province (A2017368 to PJ).
The authors declare no competing interests.
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Jiang, P., Li, Ss., Xu, Xf. et al. TRPV4 channel is involved in HSV-2 infection in human vaginal epithelial cells through triggering Ca2+ oscillation. Acta Pharmacol Sin (2022). https://doi.org/10.1038/s41401-022-00975-7
- Herpes simplex virus type 2
- TRPV4 channel
- Ca2+ signals