VIPhyb, an Antagonist of Vasoactive Intestinal Peptide Receptor, Enhances Cellular Antiviral Immunity in Murine Cytomegalovirus Infected Mice

• Type of Material: Article
• Authors: Jian-Ming Li, Emory University; Kasia A. Darlak, Emory University; Lauren Southerland, Duke University; Mohammad S Hossain, Emory University; David L Jaye, Emory University; Cassandra D Josephson, Emory University; Hilary Rosenthal, Emory University; Edmund K Waller, Emory University
• Language: English
• Date: 2013-05-27
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2013 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0063381
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 8
• Issue: 5
• Start Page: 1
• End Page: 14
• Grant/Funding Information: This work was supported by National Institutes of Health Grant R01 CA-74364-03 (to E.K.W.). J.M.L.; J.M.L. was supported by a research grant from the When Everyone Survives Foundation and the Emory University Research Council.
• Research Categories: Health Sciences, Oncology; Health Sciences, Pathology

Abstract

Vasoactive intestinal peptide (VIP) is a neuropeptide hormone that suppresses Th1-mediated cellular immunity. We previously reported that VIP-knockout (VIP-KO) mice have enhanced cellular immune responses and increased survival following murine cytomegalovirus (mCMV) infection in C57BL/6 mice. In this study, we tested whether treatment with a VIP receptor antagonistic peptide protects C57BL/6 and BALB/c mice from mCMV-infection. One week of daily subcutaneous injections of VIPhyb was non-toxic and did not alter frequencies of immune cell subsets in non-infected mice. VIPhyb administration to mCMV-infected C57BL/6 and BALB/c mice markedly enhanced survival, viral clearance, and reduced liver and lung pathology compared with saline-treated controls. The numbers of effector/memory CD8+ T-cells and mature NK cells were increased in VIPhyb-treated mice compared with PBS-treated groups. Pharmacological blockade of VIP-receptor binding or genetic blockade of VIP-signaling prevented the up-regulation of PD-L1 and PD-1 expression on DC and activated CD8+ T-cells, respectively, in mCMV-infected mice, and enhanced CD80, CD86, and MHC-II expression on conventional and plasmacytoid DC. VIPhyb-treatment increased type-I IFN synthesis, numbers of IFN-γ- and TNF-α-expressing NK cells and T-cells, and the numbers of mCMV-M45 epitope-peptide-MHC-I tetramer CD8+ T-cells following mCMV infection. VIP-treatment lowered the percentage of Treg cells in spleens compared with PBS-treated WT mice following mCMV infection, while significantly decreasing levels of serum VEGF induced by mCMV-infection. The mice in all treated groups exhibited similar levels of anti-mCMV antibody titers. Short-term administration of a VIP-receptor antagonist represents a novel approach to enhance innate and adaptive cellular immunity in a murine model of CMV infection.