Methyltransferase-defective avian metapneumovirus vaccines provide complete protection against challenge with the homologous Colorado strain and the heterologous Minnesota strain

Authors: SUN, JING - The Ohio State University; WEI, YONGWEI - The Ohio State University; RAUF, ABDUL - The Ohio State University; ZHANG, YU - The Ohio State University; MA, YUANMEI - The Ohio State University; ZHANG, XIAODONG - The Ohio State University; SHILO, KONSTANTIN - The Ohio State University; Yu, Qingzhong; SAIF, Y - The Ohio State University; LU, XINGMENG - Zhejiang University; YU, LIAN - Zhejiang University; LI, JIANRONG - The Ohio State University

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/7/2014
Publication Date: 8/13/2014
Publication URL: http://handle.nal.usda.gov/10113/60134
Citation: Sun, J., Wei, Y., Rauf, A., Zhang, Y., Ma, Y., Zhang, X., Shilo, K., Yu, Q., Saif, Y.M., Lu, X., Yu, L., Li, J. 2014. Methyltransferase-defective avian metapneumovirus vaccines provide complete protection against challenge with the homologous Colorado strain and the heterologous Minnesota strain. Journal of Virology. 88(21):12348-12363. doi: 10.1128/JVI.01095-14.

Interpretive Summary: Avian metapneumovirus (aMPV), also known as avian pneumovirus or turkey rhinotracheitis virus, is an economically important avian pathogen that can cause serious respiratory tract disease in poultry worldwide. Vaccination with live attenuated vaccines, combined with strict biosecurity, has been the routine practices for controlling the disease. Currently used aMPV vaccines in many countries were developed by multi-passages in cell culture. Although these live attenuated commercial vaccines are effective in migrating clinical disease, they appear to be not stable and can become more virulence by bird-to-bird passage and result in outbreaks of the disease in the field. To overcome the problems associated with virulence reversion of the live attenuated vaccines, we developed a novel approach to attenuate the aMPV subgroup C virus by mutating the S-adenosyl methionine binding sites in the viral polymerase gene. These genetically modified viruses were stable and highly attenuated in cell culture and in young turkeys. Vaccination of turkeys with these methyltransferase-defective aMPVs induced a high level of neutralizing antibody and conferred completely protection against challenge with homologous aMPV Colorado strain and heterologous aMPV Minnesota strain. Collectively, our results indicate that (i) aMPV lacking 2’-O methylation is highly attenuated in vitro and in vivo, and (ii) inhibition of mRNA cap methyltransferase can serve as a novel target to rationally design live attenuated vaccines for aMPV, and perhaps other paramyxoviruses.

Technical 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 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 that (i) aMPV lacking 2’-O methylation is highly attenuated in vitro and in vivo, and (ii) inhibition of mRNA cap MTase can serve as a novel target to rationally design live attenuated vaccines for aMPV, and perhaps other paramyxoviruses.