Phenotypic effects of mutations observed in the neuraminidase of human origin H5N1 influenza A viruses.
Global spread and regional endemicity of H5Nx Goose/Guangdong avian influenza viruses (AIV) pose a continuous threat for poultry production and zoonotic, potentially pre-pandemic, transmission to humans. Little is known about the role of mutations in the viral neuraminidase (NA) that accompanied bir...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-02-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1011135 |
| _version_ | 1811162584498307072 |
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| author | David Scheibner Ahmed H Salaheldin Ola Bagato Luca M Zaeck Ahmed Mostafa Ulrike Blohm Christin Müller Ahmed F Eweas Kati Franzke Axel Karger Alexander Schäfer Marcel Gischke Donata Hoffmann Solène Lerolle Xuguang Li Hatem S Abd El-Hamid Jutta Veits Angele Breithaupt Geert-Jan Boons Mikhail Matrosovich Stefan Finke Stephan Pleschka Thomas C Mettenleiter Robert P de Vries Elsayed M Abdelwhab |
| author_facet | David Scheibner Ahmed H Salaheldin Ola Bagato Luca M Zaeck Ahmed Mostafa Ulrike Blohm Christin Müller Ahmed F Eweas Kati Franzke Axel Karger Alexander Schäfer Marcel Gischke Donata Hoffmann Solène Lerolle Xuguang Li Hatem S Abd El-Hamid Jutta Veits Angele Breithaupt Geert-Jan Boons Mikhail Matrosovich Stefan Finke Stephan Pleschka Thomas C Mettenleiter Robert P de Vries Elsayed M Abdelwhab |
| author_sort | David Scheibner |
| collection | DOAJ |
| description | Global spread and regional endemicity of H5Nx Goose/Guangdong avian influenza viruses (AIV) pose a continuous threat for poultry production and zoonotic, potentially pre-pandemic, transmission to humans. Little is known about the role of mutations in the viral neuraminidase (NA) that accompanied bird-to-human transmission to support AIV infection of mammals. Here, after detailed analysis of the NA sequence of human H5N1 viruses, we studied the role of A46D, L204M, S319F and S430G mutations in virus fitness in vitro and in vivo. Although H5N1 AIV carrying avian- or human-like NAs had similar replication efficiency in avian cells, human-like NA enhanced virus replication in human airway epithelia. The L204M substitution consistently reduced NA activity of H5N1 and nine other influenza viruses carrying NA of groups 1 and 2, indicating a universal effect. Compared to the avian ancestor, human-like H5N1 virus has less NA incorporated in the virion, reduced levels of viral NA RNA replication and NA expression. We also demonstrate increased accumulation of NA at the plasma membrane, reduced virus release and enhanced cell-to-cell spread. Furthermore, NA mutations increased virus binding to human-type receptors. While not affecting high virulence of H5N1 in chickens, the studied NA mutations modulated virulence and replication of H5N1 AIV in mice and to a lesser extent in ferrets. Together, mutations in the NA of human H5N1 viruses play different roles in infection of mammals without affecting virulence or transmission in chickens. These results are important to understand the genetic determinants for replication of AIV in mammals and should assist in the prediction of AIV with zoonotic potential. |
| first_indexed | 2024-04-10T06:32:51Z |
| format | Article |
| id | doaj.art-5e67914c60d94bd3bdd8f58ed3fa88db |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-04-10T06:32:51Z |
| publishDate | 2023-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-5e67914c60d94bd3bdd8f58ed3fa88db2023-03-01T05:31:28ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742023-02-01192e101113510.1371/journal.ppat.1011135Phenotypic effects of mutations observed in the neuraminidase of human origin H5N1 influenza A viruses.David ScheibnerAhmed H SalaheldinOla BagatoLuca M ZaeckAhmed MostafaUlrike BlohmChristin MüllerAhmed F EweasKati FranzkeAxel KargerAlexander SchäferMarcel GischkeDonata HoffmannSolène LerolleXuguang LiHatem S Abd El-HamidJutta VeitsAngele BreithauptGeert-Jan BoonsMikhail MatrosovichStefan FinkeStephan PleschkaThomas C MettenleiterRobert P de VriesElsayed M AbdelwhabGlobal spread and regional endemicity of H5Nx Goose/Guangdong avian influenza viruses (AIV) pose a continuous threat for poultry production and zoonotic, potentially pre-pandemic, transmission to humans. Little is known about the role of mutations in the viral neuraminidase (NA) that accompanied bird-to-human transmission to support AIV infection of mammals. Here, after detailed analysis of the NA sequence of human H5N1 viruses, we studied the role of A46D, L204M, S319F and S430G mutations in virus fitness in vitro and in vivo. Although H5N1 AIV carrying avian- or human-like NAs had similar replication efficiency in avian cells, human-like NA enhanced virus replication in human airway epithelia. The L204M substitution consistently reduced NA activity of H5N1 and nine other influenza viruses carrying NA of groups 1 and 2, indicating a universal effect. Compared to the avian ancestor, human-like H5N1 virus has less NA incorporated in the virion, reduced levels of viral NA RNA replication and NA expression. We also demonstrate increased accumulation of NA at the plasma membrane, reduced virus release and enhanced cell-to-cell spread. Furthermore, NA mutations increased virus binding to human-type receptors. While not affecting high virulence of H5N1 in chickens, the studied NA mutations modulated virulence and replication of H5N1 AIV in mice and to a lesser extent in ferrets. Together, mutations in the NA of human H5N1 viruses play different roles in infection of mammals without affecting virulence or transmission in chickens. These results are important to understand the genetic determinants for replication of AIV in mammals and should assist in the prediction of AIV with zoonotic potential.https://doi.org/10.1371/journal.ppat.1011135 |
| spellingShingle | David Scheibner Ahmed H Salaheldin Ola Bagato Luca M Zaeck Ahmed Mostafa Ulrike Blohm Christin Müller Ahmed F Eweas Kati Franzke Axel Karger Alexander Schäfer Marcel Gischke Donata Hoffmann Solène Lerolle Xuguang Li Hatem S Abd El-Hamid Jutta Veits Angele Breithaupt Geert-Jan Boons Mikhail Matrosovich Stefan Finke Stephan Pleschka Thomas C Mettenleiter Robert P de Vries Elsayed M Abdelwhab Phenotypic effects of mutations observed in the neuraminidase of human origin H5N1 influenza A viruses. PLoS Pathogens |
| title | Phenotypic effects of mutations observed in the neuraminidase of human origin H5N1 influenza A viruses. |
| title_full | Phenotypic effects of mutations observed in the neuraminidase of human origin H5N1 influenza A viruses. |
| title_fullStr | Phenotypic effects of mutations observed in the neuraminidase of human origin H5N1 influenza A viruses. |
| title_full_unstemmed | Phenotypic effects of mutations observed in the neuraminidase of human origin H5N1 influenza A viruses. |
| title_short | Phenotypic effects of mutations observed in the neuraminidase of human origin H5N1 influenza A viruses. |
| title_sort | phenotypic effects of mutations observed in the neuraminidase of human origin h5n1 influenza a viruses |
| url | https://doi.org/10.1371/journal.ppat.1011135 |
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