Molecular basis of neurovirulence of flury rabies virus vaccine strains: importance of the polymerase and the glycoprotein R333Q mutation.
The molecular mechanisms associated with rabies virus (RV) virulence are not fully understood. In this study, the RV Flury low-egg-passage (LEP) and high-egg-passage (HEP) strains were used as models to explore the attenuation mechanism of RV. The results of our studies confirmed that the R333Q mutation in the glycoprotein (G(R333Q)) is crucial for the attenuation of Flury RV in mice. The R333Q mutation is stably maintained in the HEP genome background but not in the LEP genome background during replication in mouse brain tissue or cell culture. Further investigation using chimeric viruses revealed that the polymerase L gene determines the genetic stability of the G(R333Q) mutation during replication. Moreover, a recombinant RV containing the LEP G protein with the R333Q mutation and the HEP L gene showed significant attenuation, genetic stability, enhancement of apoptosis, and immunogenicity. These results indicate that attenuation of the RV Flury strain results from the coevolution of G and L elements and provide important information for the generation of safer and more effective modified live rabies vaccine.
Veterinary Public Health Laboratory of Ministry of Agriculture, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150001, People's Republic of China.
Lihong
L
Tao
Jinying
J
Ge
Xijun
X
Wang
Hongyue
H
Zhai
Tao
T
Hua
Bolin
B
Zhao
Dongni
D
Kong
Chinglai
C
Yang
Hualan
H
Chen
Zhigao
Z
Bu
D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000276:immunology / Q000821:virology; D002460:Cell Line; D006224:Cricetinae; D012321:DNA-Directed RNA Polymerases / Q000235:genetics / Q000378:metabolism*; D004283:Dog Diseases / Q000276:immunology / Q000821:virology*; D004285:Dogs; D005260:Female; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011818:Rabies / Q000276:immunology / Q000662:veterinary* / Q000821:virology; D011819:Rabies Vaccines / Q000235:genetics* / Q000276:immunology; D011820:Rabies virus / Q000201:enzymology / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014774:Virulence; D014779:Virus Replication
D006023:Glycoproteins; D011819:Rabies Vaccines; D014764:Viral Proteins; C097625:L protein, Rabies virus; D012321:DNA-Directed RNA Polymerases