Vaccine-modified NF-kB and GR signaling in cervicovaginal epithelium correlates with protection.

• Type of Material: Article
• Authors: L. Shang, University of Minnesota; A. J. Smith, University of Minnesota; C. S. Reilly, University of Minnesota; L. Duan, University of Minnesota; K. E. Perkey, University of Minnesota; S. Wietgrefe, University of Minnesota; M. Zupancic, University of Minnesota; P. J. Southern, University of Minnesota; R. Paul Johnson, Emory University; J. V. Carlis, University of Minnesota; A. T. Haase, University of Minnesota
• Language: English
• Date: 2017-08-09
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Society for Mucosal Immunology
• Final Published Version (URL): http://dx.doi.org/10.1038/mi.2017.69
• Title of Journal or Parent Work: Mucosal Immunology
• ISSN: 1933-0219
• Grant/Funding Information: This work was supported by the International AIDS Vaccine Initiative, National Institutes of Health grants AI071306 and RR00168, and in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E.
• Keywords: Female Reproductive Tract; Epithelium; Glucocorticoid Receptor; Mucosa; Mucosal Transmission; Vagina; SIV; NF-kB; Cervix; SIVΔnef; Vaginal Infection
• Research Categories: Biology, Microbiology; Health Sciences, Immunology

Abstract

Cervicovaginal epithelium plays a critical role in determining the outcome of virus transmission in the female reproductive tract (FRT) by initiating or suppressing transmission-facilitating mucosal immune responses in naïve and SIVmac239Δnef-vaccinated animals, respectively. In this study, we examined the very early responses of cervical epithelium within 24 h after vaginal exposure to SIV in naive and SIVmac239Δnef-vaccinated rhesus macaques. Using both ex vivo and in vivo experimental systems, we found that vaginal exposure to SIV rapidly induces a broad spectrum of pro-inflammatory responses in the epithelium associated with a reciprocal regulation of NF-kB and glucocorticoid receptor (GR) signaling pathways. Conversely, maintenance of high-level GR expression and suppression of NF-kB expression in the epithelium were associated with an immunologically quiescent state in the FRT mucosa and protection against vaginal challenge in SIVmac239Δnef-vaccinated animals. We show that the immunologically quiescent state is induced by FCGR2B-immune complexes interactions that modify the reciprocal regulation of NF-kB and GR signaling pathways. Our results suggest that targeting the balance of NF-kB and GR signaling in early cervicovaginal epithelium responses could moderate mucosal inflammation and target cell availability after vaginal infection, thereby providing a complementary approach to current prevention strategies.