期刊
EMERGING MICROBES & INFECTIONS
卷 10, 期 1, 页码 2052-2061出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/22221751.2021.1997340
关键词
Influenza virus; molecular basis; pathogenicity; mice
资金
- National Natural Science Foundation of China [31521005]
- National Key Research and Development Program of China [2016YFD0500203]
- China Agriculture Research System [CARS-41-G12]
- Central Public-interest Scientific Institution Basal Research Fund [1610302017001]
- Japan Initiative for Global Research Network on Infectious Diseases from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan
This study characterized two H5N6 avian influenza viruses with different lethality in mice, attributing the difference in virulence to a mutation in the HA gene. The mutation G225W in the HA protein decreased the stability and increased the activation pH of the virus, providing a potential target for the development of vaccines and drugs against H5 influenza viruses.
The highly pathogenic avian influenza H5N6 viruses are widely circulating in poultry and wild birds, and have caused 38 human infections including 21 deaths; however, the key genetic determinants of the pathogenicity of these viruses have yet to be fully investigated. Here, we characterized two H5N6 avian influenza viruses - A/duck/Guangdong/S1330/2016 (GD/330) and A/environment/Fujian/S1160/2016 (FJ/160) - that have similar viral genomes but differ markedly in their lethality in mice. GD/330 is highly pathogenic with a 50% mouse lethal dose (MLD50) of 2.5 log(10) 50% egg infectious doses (EID50), whereas FJ/160 exhibits low pathogenicity with an MLD50 of 7.4 log(10) EID50. We explored the molecular basis for the difference in virulence between these two viruses. By using reverse genetics, we created a series of reassortants and mutants in the GD/330 background and assessed their virulence in mice. We found that the HA gene of FJ/160 substantially attenuated the virulence of GD/330 and that the mutation of glycine (G) to tryptophan (W) at position 225 (H3 numbering) in HA played a key role in this function. We further found that the amino acid mutation G225W in HA decreased the acid and thermal stability and increased the pH of HA activation, thereby attenuating the H5N6 virus in mice. Our study thus identifies a novel molecular determinant in the HA protein and provides a new target for the development of live attenuated vaccines and antiviral drugs against H5 influenza viruses.
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