Identification of key hemagglutinin residues responsible for cleavage, acid stability, and virulence of fifth-wave highly pathogenic avian influenza A(H7N9) viruses

We previously demonstrated that despite no airborne transmissibility increase compared to low pathogenic avian influenza viruses, select human isolates of highly pathogenic avian influenza A(H7N9) virus exhibit greater virulence in animal models and a lower threshold pH for fusion. In the current st...

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Bibliographic Details
Published in:Virology (New York, N.Y.) N.Y.), 2019-09, Vol.535, p.232-240
Main Authors: Sun, Xiangjie, Belser, Jessica A., Yang, Hua, Pulit-Penaloza, Joanna A., Pappas, Claudia, Brock, Nicole, Zeng, Hui, Creager, Hannah M., Stevens, James, Maines, Taronna R.
Format: Article
Language:English
Subjects:
A(H7N9)
Acid stability
Animals
Disease Models, Animal
DNA Mutational Analysis
Fusion
Hemagglutinin cleavage
Hemagglutinin Glycoproteins, Influenza Virus - chemistry
Hemagglutinin Glycoproteins, Influenza Virus - genetics
Hemagglutinin Glycoproteins, Influenza Virus - metabolism
Humans
Hydrogen-Ion Concentration
Influenza A Virus, H7N9 Subtype - genetics
Influenza A Virus, H7N9 Subtype - growth & development
Influenza A Virus, H7N9 Subtype - isolation & purification
Influenza virus
Influenza, Human - virology
Mice
Orthomyxoviridae Infections - pathology
Orthomyxoviridae Infections - virology
Protein Stability
Proteolysis
Virulence
Virulence Factors - chemistry
Virulence Factors - genetics
Virulence Factors - metabolism
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Summary:We previously demonstrated that despite no airborne transmissibility increase compared to low pathogenic avian influenza viruses, select human isolates of highly pathogenic avian influenza A(H7N9) virus exhibit greater virulence in animal models and a lower threshold pH for fusion. In the current study, we utilized both in vitro and in vivo approaches to identify key residues responsible for hemagglutinin (HA) intracellular cleavage, acid stability, and virulence in mice. We found that the four amino acid insertion (-KRTA-) at the HA cleavage site of A/Taiwan/1/2017 virus is essential for HA intracellular cleavage and contributes to disease in mice. Furthermore, a lysine to glutamic acid mutation at position HA2-64 increased the threshold pH for HA activation, reduced virus stability, and replication in mice. Identification of a key residue responsible for enhanced acid stability of A(H7N9) viruses is of great significance for future surveillance activities and improvements in vaccine stability.
ISSN:0042-6822
1096-0341
DOI:10.1016/j.virol.2019.07.012