Reduced levels of neuraminidase of influenza A viruses correlate with attenuated phenotypes in mice.
We have previously obtained four transfectant influenza A viruses containing neuraminidase (NA) genes with mutated base pairs in the conserved double-stranded RNA region of the viral promoter by using a ribonucleoprotein transfection system. Two mutant viruses (D2 and D1/2) which share a C-G-->A-U mutation at positions 11 and 12 of the 3' and 5' ends, respectively, of the NA gene, showed an approximate 10-fold reduction of NA-specific mRNA and protein levels (Fodor et al., Journal of Virology 72, 6283-6290, 1998). These viruses have now allowed us to determine the effects of decreased NA levels on virus pathogenicity. Both D2 and D1/2 viruses were highly attenuated in mice, and their replication in mouse lungs was highly compromised as compared with wild-type influenza A/WSN/33 virus. The results highlight the importance of the level of NA activity in the biological cycle and virulence of influenza viruses. Importantly, mice immunized by a single intranasal administration of 10(3) infectious units of D2 or D1/2 viruses were protected against challenge with a lethal dose of wild-type influenza virus. Attenuation of influenza viruses by mutations resulting in the decreased expression of a viral protein represents a novel strategy which could be considered for the generation of live attenuated influenza virus vaccines.
Solorzano
A
A
Department of Microbiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6574, USA.
Zheng
H
H
Fodor
E
E
Brownlee
G G
GG
Palese
P
P
García-Sastre
A
A
D000818:Animals; D002460:Cell Line; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D007114:Immunization; D009980:Influenza A virus / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity*; D007252:Influenza Vaccines / Q000235:genetics; D008168:Lung / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009439:Neuraminidase / Q000235:genetics / Q000378:metabolism*; D009976:Orthomyxoviridae Infections / Q000517:prevention & control; D010641:Phenotype; D014162:Transfection; D014613:Vaccines, Attenuated / Q000235:genetics; D014774:Virulence / Q000235:genetics / Q000502:physiology; D014779:Virus Replication / Q000235:genetics / Q000502:physiology
D004279:DNA, Viral; D007252:Influenza Vaccines; D014613:Vaccines, Attenuated; D009439:Neuraminidase