PMID- 29643245
OWN - NLM
STAT- MEDLINE
DCOM- 20180730
LR  - 20191210
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 92
IP  - 13
DP  - 2018 Jul 1
TI  - Recombinant Porcine Reproductive and Respiratory Syndrome Virus Expressing 
      Membrane-Bound Interleukin-15 as an Immunomodulatory Adjuvant Enhances NK and gammadelta 
      T Cell Responses and Confers Heterologous Protection.
LID - 10.1128/JVI.00007-18 [doi]
LID - e00007-18
AB  - Cytokines are often used as adjuvants to improve vaccine immunogenicity, since 
      they are important in initiating and shaping the immune response. The available 
      commercial modified live-attenuated vaccines (MLVs) against porcine reproductive 
      and respiratory syndrome virus (PRRSV) are unable to mount sufficient 
      heterologous protection, as they typically induce weak innate and inadequate T 
      cell responses. In this study, we investigated the immunogenicity and vaccine 
      efficacy of recombinant PRRSV MLVs incorporated with the porcine cytokine 
      interleukin-15 (IL-15) or IL-18 gene fused to a glycosylphosphatidylinositol 
      (GPI) modification signal that can anchor the cytokines to the cell membrane. We 
      demonstrated that both cytokines were successfully expressed on the cell membrane 
      of porcine alveolar macrophages after infection with recombinant MLVs. Pigs 
      vaccinated with recombinant MLVs or the parental Suvaxyn MLV had significantly 
      reduced lung lesions and viral RNA loads in the lungs after heterologous 
      challenge with the PRRSV NADC20 strain. The recombinant MLVs SUV-IL-15 and 
      SUV-IL-18 recovered the inhibition of the NK cell response seen with Suvaxyn MLV. 
      The recombinant MLV SUV-IL-15 significantly increased the numbers of gamma 
      interferon (IFN-gamma)-producing cells in circulation at 49 days postvaccination 
      (dpv), especially for IFN-gamma-producing CD4(-) CD8(+) T cells and gammadelta T cells, 
      compared to the Suvaxyn MLV and SUV-IL-18. Additionally, MLV SUV-IL-15-vaccinated 
      pigs also had elevated levels of gammadelta T cell responses observed at 7 dpv, 49 dpv, 
      and 7 days postchallenge. These data demonstrate that the recombinant MLV 
      expressing membrane-bound IL-15 enhances NK and T cell immune responses after 
      vaccination and confers improved heterologous protection, although this was not 
      statistically significant compared to the parental MLV.IMPORTANCE Porcine 
      reproductive and respiratory syndrome (PRRS) has arguably been the most 
      economically important global swine disease, causing immense economic losses 
      worldwide. The available commercial modified live-attenuated vaccines (MLVs) 
      against PRRS virus (PRRSV) are generally effective against only homologous or 
      closely related virus strains but are ineffective against heterologous strains, 
      partially due to the insufficient immune response induced by the vaccine virus. 
      To improve the immunogenicity of MLVs, in this study, we present a novel approach 
      of using porcine IL-15 or IL-18 as an adjuvant by directly incorporating its 
      encoding gene into a PRRSV MLV and expressing it as an adjuvant. Importantly, we 
      directed the expression of the incorporated cytokines to the cell membrane 
      surface by fusing the genes with a membrane-targeting signal from CD59. The 
      recombinant MLV virus expressing the membrane-bound IL-15 cytokine greatly 
      enhanced NK cell and gammadelta T cell responses and also conferred improved protection 
      against heterologous challenge with the PRRSV NADC20 strain.
CI  - Copyright (c) 2018 American Society for Microbiology.
FAU - Cao, Qian M
AU  - Cao QM
AD  - Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of 
      Veterinary Medicine, Virginia Polytechnic Institute and State University 
      (Virginia Tech), Blacksburg, Virginia, USA.
FAU - Ni, Yan-Yan
AU  - Ni YY
AD  - Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of 
      Veterinary Medicine, Virginia Polytechnic Institute and State University 
      (Virginia Tech), Blacksburg, Virginia, USA.
FAU - Cao, Dianjun
AU  - Cao D
AD  - Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of 
      Veterinary Medicine, Virginia Polytechnic Institute and State University 
      (Virginia Tech), Blacksburg, Virginia, USA.
FAU - Tian, Debin
AU  - Tian D
AD  - Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of 
      Veterinary Medicine, Virginia Polytechnic Institute and State University 
      (Virginia Tech), Blacksburg, Virginia, USA.
FAU - Yugo, Danielle M
AU  - Yugo DM
AD  - Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of 
      Veterinary Medicine, Virginia Polytechnic Institute and State University 
      (Virginia Tech), Blacksburg, Virginia, USA.
FAU - Heffron, C Lynn
AU  - Heffron CL
AD  - Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of 
      Veterinary Medicine, Virginia Polytechnic Institute and State University 
      (Virginia Tech), Blacksburg, Virginia, USA.
FAU - Overend, Christopher
AU  - Overend C
AD  - Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of 
      Veterinary Medicine, Virginia Polytechnic Institute and State University 
      (Virginia Tech), Blacksburg, Virginia, USA.
FAU - Subramaniam, Sakthivel
AU  - Subramaniam S
AD  - Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of 
      Veterinary Medicine, Virginia Polytechnic Institute and State University 
      (Virginia Tech), Blacksburg, Virginia, USA.
FAU - Rogers, Adam J
AU  - Rogers AJ
AD  - Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of 
      Veterinary Medicine, Virginia Polytechnic Institute and State University 
      (Virginia Tech), Blacksburg, Virginia, USA.
FAU - Catanzaro, Nicholas
AU  - Catanzaro N
AD  - Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of 
      Veterinary Medicine, Virginia Polytechnic Institute and State University 
      (Virginia Tech), Blacksburg, Virginia, USA.
FAU - LeRoith, Tanya
AU  - LeRoith T
AD  - Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of 
      Veterinary Medicine, Virginia Polytechnic Institute and State University 
      (Virginia Tech), Blacksburg, Virginia, USA.
FAU - Roberts, Paul C
AU  - Roberts PC
AD  - Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of 
      Veterinary Medicine, Virginia Polytechnic Institute and State University 
      (Virginia Tech), Blacksburg, Virginia, USA.
FAU - Meng, Xiang-Jin
AU  - Meng XJ
AD  - Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of 
      Veterinary Medicine, Virginia Polytechnic Institute and State University 
      (Virginia Tech), Blacksburg, Virginia, USA xjmeng@vt.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180613
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Adjuvants, Immunologic)
RN  - 0 (Antibodies, Neutralizing)
RN  - 0 (Antibodies, Viral)
RN  - 0 (Interleukin-15)
RN  - 0 (Viral Vaccines)
SB  - IM
MH  - *Adjuvants, Immunologic
MH  - Animals
MH  - Antibodies, Neutralizing/immunology
MH  - Antibodies, Viral/blood/immunology
MH  - Chlorocebus aethiops
MH  - Host-Pathogen Interactions
MH  - Interleukin-15/immunology/*metabolism
MH  - Kidney/immunology/virology
MH  - Killer Cells, Natural/*immunology/virology
MH  - Lung Diseases/immunology/*prevention & control/virology
MH  - Porcine Reproductive and Respiratory Syndrome/immunology/*prevention & 
      control/virology
MH  - Porcine respiratory and reproductive syndrome virus/genetics/immunology
MH  - Swine
MH  - T-Lymphocytes/*immunology/virology
MH  - Vaccination
MH  - Viral Vaccines/*administration & dosage
MH  - Viremia/immunology/virology
PMC - PMC6002708
OTO - NOTNLM
OT  - MLV
OT  - NK cells
OT  - adjuvant
OT  - immunogenicity
OT  - membrane-bound IL-15
OT  - modified live-attenuated vaccine
OT  - gammadelta T cells
EDAT- 2018/04/13 06:00
MHDA- 2018/07/31 06:00
PMCR- 2018/12/13
CRDT- 2018/04/13 06:00
PHST- 2018/01/04 00:00 [received]
PHST- 2018/04/09 00:00 [accepted]
PHST- 2018/04/13 06:00 [pubmed]
PHST- 2018/07/31 06:00 [medline]
PHST- 2018/04/13 06:00 [entrez]
PHST- 2018/12/13 00:00 [pmc-release]
AID - JVI.00007-18 [pii]
AID - 00007-18 [pii]
AID - 10.1128/JVI.00007-18 [doi]
PST - epublish
SO  - J Virol. 2018 Jun 13;92(13):e00007-18. doi: 10.1128/JVI.00007-18. Print 2018 Jul 
      1.