title: 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-β 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-β within CXCL9 promoter sequence. Furthermore, CXCL9 expression is promoted at the transcriptional level through phosphorylating C/EBP-β via p38 MAPK pathway, leading to binding of C/EBP-β 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-β 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-β pathway through promoting the binding of C/EBP-β 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.
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Huang
authors.forename: Kai
authors.initials: K
authors.lastname: Hu
authors.forename: Sukun
authors.initials: S
authors.lastname: Luo
authors.forename: Mudan
authors.initials: M
authors.lastname: Zhang
authors.forename: Chang
authors.initials: C
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Jin
authors.forename: Yalan
authors.initials: Y
authors.lastname: Liu
authors.forename: George E
authors.initials: GE
authors.lastname: Griffin
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Shattock
authors.forename: Qinxue
authors.initials: Q
authors.lastname: Hu
mesh_terms: D000328:Adult; D015153:Blotting, Western; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002584:Cervix Uteri / Q000821:virology; D054370:Chemokine CXCL9 / Q000096:biosynthesis* / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006561:Herpes Simplex / Q000276:immunology / Q000378:metabolism*; D018258:Herpesvirus 2, Human / Q000276:immunology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D055815:Young Adult
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C080810:CXCL9 protein, human; D054370:Chemokine CXCL9