Herpes simplex virus type 2 infection of human epithelial cells induces CXCL9 expression and CD4+ T cell migration via activation of p38-CCAAT/enhancer-binding protein-ß pathway.

ABSTRACT

Recruitment of CD4(+) T cells to infection areas after HSV-2 infection may be one of the mechanisms that account for increased HIV-1 sexual transmission. Lymphocytes recruited by chemokine CXCL9 are known to be important in control of HSV-2 infection in mice, although the underlying mechanism remains to be addressed. Based on our observation that CXCL9 expression is augmented in the cervical mucus of HSV-2-positive women, in this study we demonstrate that HSV-2 infection directly induces CXCL9 expression in primary cervical epithelial cells and cell lines, the principal targets of HSV-2, at both mRNA and protein levels. Further studies reveal that the induction of CXCL9 expression by HSV-2 is dependent upon a binding site for C/EBP-ß within CXCL9 promoter sequence. Furthermore, CXCL9 expression is promoted at the transcriptional level through phosphorylating C/EBP-ß via p38 MAPK pathway, leading to binding of C/EBP-ß to the CXCL9 promoter. Chemotaxis assays indicate that upregulation of CXCL9 expression at the protein level by HSV-2 infection enhances the migration of PBLs and CD4(+) T cells, whereas neutralization of CXCL9 or inhibition of p38-C/EBP-ß pathway can significantly decrease the migration. Our data together demonstrate that HSV-2 induces CXCL9 expression in human cervical epithelial cells by activation of p38-C/EBP-ß pathway through promoting the binding of C/EBP-ß to CXCL9 promoter, which may recruit activated CD4(+) T cells to mucosal HSV-2 infection sites and potentially increase the risk of HIV-1 sexual transmission.