title: Methyltransferase-defective avian metapneumovirus vaccines provide complete protection against challenge with the homologous Colorado strain and the heterologous Minnesota strain.
abstract: Avian metapneumovirus (aMPV), also known as avian pneumovirus or turkey rhinotracheitis virus, is the causative agent of turkey rhinotracheitis and is associated with swollen head syndrome in chickens. Since its discovery in the 1970s, aMPV has been recognized as an economically important pathogen in the poultry industry worldwide. The conserved region VI (CR VI) of the large (L) polymerase proteins of paramyxoviruses catalyzes methyltransferase (MTase) activities that typically methylate viral mRNAs at guanine N-7 (G-N-7) and ribose 2'-O positions. In this study, we generated a panel of recombinant aMPV (raMPV) Colorado strains carrying mutations in the S-adenosyl methionine (SAM) binding site in the CR VI of L protein. These recombinant viruses were specifically defective in ribose 2'-O, but not G-N-7 methylation and were genetically stable and highly attenuated in cell culture and viral replication in the upper and lower respiratory tracts of specific-pathogen-free (SPF) young turkeys. Importantly, turkeys vaccinated with these MTase-defective raMPVs triggered a high level of neutralizing antibody and were completely protected from challenge with homologous aMPV Colorado strain and heterologous aMPV Minnesota strain. Collectively, our results indicate (i) that aMPV lacking 2'-O methylation is highly attenuated in vitro and in vivo and (ii) that inhibition of mRNA cap MTase can serve as a novel target to rationally design live attenuated vaccines for aMPV and perhaps other paramyxoviruses.
  
  
  OBJECTIVE
  Paramyxoviruses include many economically and agriculturally important viruses such as avian metapneumovirus (aMPV), and Newcastle disease virus (NDV), human pathogens such as human respiratory syncytial virus, human metapneumovirus, human parainfluenza virus type 3, and measles virus, and highly lethal emerging pathogens such as Nipah virus and Hendra virus. For many of them, there is no effective vaccine or antiviral drug. These viruses share common strategies for viral gene expression and replication. During transcription, paramyxoviruses produce capped, methylated, and polyadenylated mRNAs. Using aMPV as a model, we found that viral ribose 2'-O methyltransferase (MTase) is a novel approach to rationally attenuate the virus for vaccine purpose. Recombinant aMPV (raMPV) lacking 2'-O MTase were not only highly attenuated in turkeys but also provided complete protection against the challenge of homologous and heterologous aMPV strains. This novel approach can be applicable to other animal and human paramyxoviruses for rationally designing live attenuated vaccines.
authors.affiliation: Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA College of Animal Science, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Yongwei
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Wooster, Ohio, USA.
authors.forename: Abdul
authors.initials: A
authors.lastname: Rauf
authors.affiliation: Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Yuanmei
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology, College of Medicine, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Shilo
authors.affiliation: Southeast Poultry Research Laboratory, USDA Agricultural Research Service, Athens, Georgia, USA.
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Wooster, Ohio, USA.
authors.forename: Y M
authors.initials: YM
authors.lastname: Saif
authors.affiliation: College of Animal Science, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Xingmeng
authors.initials: X
authors.lastname: Lu
authors.affiliation: College of Animal Science, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Lian
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA li.926@osu.edu.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D056738:Cross Protection; D008168:Lung / Q000821:virology; D029121:Metapneumovirus / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D008780:Methyltransferases / Q000172:deficiency; D018184:Paramyxoviridae Infections / Q000517:prevention & control / Q000662:veterinary* / Q000821:virology; D011201:Poultry Diseases / Q000517:prevention & control* / Q000821:virology*; D014132:Trachea / Q000821:virology; D014422:Turkeys; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D019562:Viral Load; D014765:Viral Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D014613:Vaccines, Attenuated; D014765:Viral Vaccines; D008780:Methyltransferases