TY - JOUR
T1 - Phenotypic effects of mutations observed in the neuraminidase of human origin H5N1 influenza A viruses
AU - Scheibner, David
AU - Salaheldin, Ahmed H.
AU - Bagato, Ola
AU - Zaeck, Luca M.
AU - Mostafa, Ahmed
AU - Blohm, Ulrike
AU - Müller, Christin
AU - Eweas, Ahmed F.
AU - Franzke, Kati
AU - Karger, Axel
AU - Schäfer, Alexander
AU - Gischke, Marcel
AU - Hoffmann, Donata
AU - Lerolle, Solène
AU - Li, Xuguang
AU - Abd El-Hamid, Hatem S.
AU - Veits, Jutta
AU - Breithaupt, Angele
AU - Boons, Geert Jan
AU - Matrosovich, Mikhail
AU - Finke, Stefan
AU - Pleschka, Stephan
AU - Mettenleiter, Thomas C.
AU - de Vries, Robert P.
AU - Abdelwhab, Elsayed M.
N1 - Funding: This project was partially funded by grants from the Deutsche Forschungsgemeinschaft (VE780/1-1, AB 567) to EMA and the DELTA-FLU Project (ID: 727922)
funded by the European Union to EMA and TCM as well as the German Centre for Infection Research (DZIF), partner site Giessen, Germany (TTU 01.806
Broad-spectrum Antivirals and FF 01.901
Publisher Copyright: © 2023 Scheibner et al.
PY - 2023/2/6
Y1 - 2023/2/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85148303564&partnerID=8YFLogxK
U2 - 10.1371/journal.ppat.1011135
DO - 10.1371/journal.ppat.1011135
M3 - Article
C2 - 36745654
AN - SCOPUS:85148303564
SN - 1553-7366
VL - 19
JO - PLoS Pathogens
JF - PLoS Pathogens
IS - 2
M1 - e1011135
ER -