title: VIPhyb, an antagonist of vasoactive intestinal peptide receptor, enhances cellular antiviral immunity in murine cytomegalovirus infected mice.
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.
authors.affiliation: Department of Hematology/Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Li
authors.forename: Kasia A
authors.initials: KA
authors.lastname: Darlak
authors.forename: Lauren
authors.initials: L
authors.lastname: Southerland
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Hossain
authors.forename: David L
authors.initials: DL
authors.lastname: Jaye
authors.forename: Cassandra D
authors.initials: CD
authors.lastname: Josephson
authors.forename: Hilary
authors.initials: H
authors.lastname: Rosenthal
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Waller
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000188:drug therapy / Q000276:immunology*; D007111:Immunity, Cellular / Q000187:drug effects*; D018836:Inflammation Mediators / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000473:pathology / Q000821:virology; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000821:virology; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009336:Necrosis / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D009496:Neurotensin / Q000494:pharmacology*; D018005:Receptors, Vasoactive Intestinal Peptide / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*; D019562:Viral Load / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D018836:Inflammation Mediators; D018005:Receptors, Vasoactive Intestinal Peptide; D011993:Recombinant Fusion Proteins; C069189:(VIP-neurotensin) hybrid antagonist; D014660:Vasoactive Intestinal Peptide; D009496:Neurotensin