HSV-2 increases TLR4-dependent phosphorylated IRFs and IFN-beta induction in cervical epithelial cells (INM9P.460)

Abstract

Abstract The innate immune pathway in response to HSV-2 in its natural host cells remains unclear. Our study has established an in vitro HSV-2 acute infection model with Human Cervical Epithelial (HCE) cells to investigate the role of TLRs-mediated innate immune response to HSV-2. Our previous studies demonstrated that HSV-2 infection up-regulates TLR4 expression and induces NF-kB activity, thereby facilitating innate immune response in human cervical epithelial cells. This process requires involvement of TLR4 adaptors, Mal and MyD88. In the current study, we found that HSV-2 infection increases levels of phosphoryalted IRF3 and IRF7, then regulating expression of type I IFN. As expected, these changes induced by HSV-2 infection depended upon TLR4. To study involvement of the downstream adaptors, we found that overexpression of TRIF and /or TRAM further increased induction of NF-kB activity, while siRNA experiments demonstrated that adaptor molecules TRIF and TRAM were also required for the TLR4-mediated both NF-kB activity and expression of IFN-beta. Our results demonstrate for the first time that IRF3 and IRF7 are both involved in inducing TLR4-dependent IFN- beta expression in response to HSV-2 in its primary infected genital epithelial cells. Thus, TLR4-Mal/MyD88 and TLR4-TRIF/TRAM signaling may synergize and /or cooperate in innate immune response of cervical epithelial cells to HSV-2 infection. (This work was supported by National Natural Science Foundation of China 81072419)