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Analysis of the Evolution of Pandemic Influenza A(H1N1) Virus Neuraminidase Reveals Entanglement of Different Phenotypic Characteristics.

Authors :
Dai M
Du W
Martínez-Romero C
Leenders T
Wennekes T
Rimmelzwaan GF
van Kuppeveld FJM
Fouchier RAM
Garcia-Sastre A
de Vries E
de Haan CAM
Source :
MBio [mBio] 2021 May 11; Vol. 12 (3). Date of Electronic Publication: 2021 May 11.
Publication Year :
2021

Abstract

The influenza A virus (IAV) neuraminidase (NA) is essential for virion release from cells and decoy receptors and an important target of antiviral drugs and antibodies. Adaptation to a new host sialome and escape from the host immune system are forces driving the selection of mutations in the NA gene. Phylogenetic analysis shows that until 2015, 16 amino acid substitutions in NA became fixed in the virus population after introduction in the human population of the pandemic IAV H1N1 (H1N1pdm09) in 2009. The accumulative effect of these substitutions, in the order in which they appeared, was analyzed using recombinant proteins and viruses in combination with different functional assays. The results indicate that NA activity did not evolve to a single optimum but rather fluctuated within a certain bandwidth. Furthermore, antigenic and enzymatic properties of NA were intertwined, with several residues affecting multiple properties. For example, the substitution K432E in the second sialic acid binding site, next to the catalytic site, was shown to affect catalytic activity, substrate specificity, and the pH optimum for maximum activity. This substitution also altered antigenicity of NA, which may explain its selection. We propose that the entanglement of NA phenotypes may be an important determining factor in the evolution of NA. IMPORTANCE Since its emergence in 2009, the pandemic H1N1 influenza A virus (IAV) has caused significant disease and mortality in humans. IAVs contain two envelope glycoproteins, the receptor-binding hemagglutinin (HA) and the receptor-destroying neuraminidase (NA). NA is essential for virion release from cells and decoy receptors, is an important target of antiviral drugs, and is increasingly being recognized as an important vaccine antigen. Not much is known, however, about the evolution of this protein upon the emergence of the novel pandemic H1N1 virus, with respect to its enzymatic activity and antigenicity. By reconstructing the evolutionary path of NA, we show that antigenic and enzymatic properties of NA are intertwined, with several residues affecting multiple properties. Understanding the entanglement of NA phenotypes will lead to better comprehension of IAV evolution and may help the development of NA-based vaccines.<br /> (Copyright © 2021 Dai et al.)

Details

Language :
English
ISSN :
2150-7511
Volume :
12
Issue :
3
Database :
MEDLINE
Journal :
MBio
Publication Type :
Academic Journal
Accession number :
33975931
Full Text :
https://doi.org/10.1128/mBio.00287-21