SUMOylation of matrix protein M1 and filamentous morphology collectively contribute to the replication and virulence of highly pathogenic H5N1 avian influenza viruses in mammals

The matrix protein (M1) of influenza A virus plays an important role in replication, assembly, and budding. A previous study found that aspartic acid (D) at position 30 and alanine (A) at position 215 of M1 contribute to the high pathogenicity of H5N1 viruses in mice, and double mutations of D to asparagine (N) at position 30 (D30N) and A to threonine (T) at position 215 (A215T) in M1 dramatically attenuate H5N1 viruses in mice. However, the underlying mechanisms by which these M1 mutations attenuate the virulence of H5N1 viruses are unknown. Here, we found that the amino acid mutation A215T eliminates the SUMOylation of M1 by reducing its interaction with the host SUMO1 protein, significantly reducing the stability of M1, slowing the export of the M1-vRNP complex from the nucleus to the cytoplasm, and reducing viral replication in MDCK cells. We further found that the D30N mutation in M1 alters the shape of progeny viruses from filamentous to spherical virions. Our findings reveal an essential role for M1 215A SUMOylation and M1 30D-related filamentous morphology in the pathogenesis of avian influenza viruses, which could be targeted in novel antiviral drug designs. Importance Identification of the pathogenic mechanism of highly pathogenic avian influenza viruses in mammals is helpful to develop novel anti-influenza virus strategies. Two amino acid mutations (D30N and A215T) in M1 were found to collectively attenuate H5N1 influenza viruses in mice, but the underlying mechanism remained unknown. This study found that the A215T mutation significantly decreases the SUMOylation of M1, which in turn attenuates the replication of H5N1 virus in mammalian cells. The D30N mutation in M1 was found to change the virion shape from filamentous to spherical. These findings are important for understanding the molecular mechanism of virulence of highly pathogenic avian influenza viruses in mammals.

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Pseudotyping of vesicular stomatitis virus with the envelope glycoproteins of highly pathogenic avian influenza viruses

Journal of General Virology ◽

10.1099/vir.0.065201-0 ◽

2014 ◽

Vol 95 (8) ◽

pp. 1634-1639 ◽

Cited By ~ 18

Author(s):

Gert Zimmer ◽

Samira Locher ◽

Marianne Berger Rentsch ◽

Stefan J. Halbherr

Keyword(s):

Avian Influenza ◽

Vesicular Stomatitis Virus ◽

Matrix Protein ◽

Highly Pathogenic Avian Influenza ◽

Influenza Viruses ◽

Envelope Glycoproteins ◽

Avian Influenza Viruses ◽

Highly Pathogenic ◽

Pathogenic Avian Influenza ◽

Vesicular Stomatitis

Pseudotype viruses are useful for studying the envelope proteins of harmful viruses. This work describes the pseudotyping of vesicular stomatitis virus (VSV) with the envelope glycoproteins of highly pathogenic avian influenza viruses. VSV lacking the homotypic glycoprotein (G) gene (VSVΔG) was used to express haemagglutinin (HA), neuraminidase (NA) or the combination of both. Propagation-competent pseudotype viruses were only obtained when HA and NA were expressed from the same vector genome. Pseudotype viruses containing HA from different H5 clades were neutralized specifically by immune sera directed against the corresponding clade. Fast and sensitive reading of test results was achieved by vector-mediated expression of GFP. Pseudotype viruses expressing a mutant VSV matrix protein showed restricted spread in IFN-competent cells. This pseudotype system will facilitate the detection of neutralizing antibodies against virulent influenza viruses, circumventing the need for high-level biosafety containment.

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Domestic ducks play a major role in the maintenance and spread of H5N8 highly pathogenic avian influenza viruses in South Korea

Transboundary and Emerging Diseases ◽

10.1111/tbed.13406 ◽

2019 ◽

Vol 67 (2) ◽

pp. 844-851 ◽

Cited By ~ 5

Author(s):

Jung‐Hoon Kwon ◽

Justin Bahl ◽

David E. Swayne ◽

Yu‐Na Lee ◽

Youn‐Jeong Lee ◽

...

Keyword(s):

Avian Influenza ◽

South Korea ◽

Highly Pathogenic Avian Influenza ◽

Influenza Viruses ◽

Avian Influenza Viruses ◽

Domestic Ducks ◽

Highly Pathogenic ◽

Pathogenic Avian Influenza

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Two amino acid residues in the matrix protein M1 contribute to the virulence difference of H5N1 avian influenza viruses in mice

Virology ◽

10.1016/j.virol.2008.11.044 ◽

2009 ◽

Vol 384 (1) ◽

pp. 28-32 ◽

Cited By ~ 129

Author(s):

Shufang Fan ◽

Guohua Deng ◽

Jiasheng Song ◽

Guobin Tian ◽

Yongbing Suo ◽

...

Keyword(s):

Amino Acid ◽

Avian Influenza ◽

Matrix Protein ◽

Influenza Viruses ◽

Amino Acid Residues ◽

Avian Influenza Viruses ◽

H5n1 Avian Influenza ◽

The Matrix ◽

Matrix Protein M1

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Opposite outcomes of the within-host competition between highly and low pathogenic H5N8 avian influenza viruses in chickens compared to ducks

Journal of Virology ◽

10.1128/jvi.01366-21 ◽

2021 ◽

Author(s):

Pierre Bessière ◽

Thomas Figueroa ◽

Amelia Coggon ◽

Charlotte Foret-Lucas ◽

Alexandre Houffschmitt ◽

...

Keyword(s):

Avian Influenza ◽

Reverse Genetics ◽

Highly Pathogenic Avian Influenza ◽

Viral Evolution ◽

Influenza Viruses ◽

Poultry Production ◽

Avian Influenza Viruses ◽

Highly Pathogenic ◽

Pathogenic Avian Influenza ◽

Low Pathogenic Avian Influenza

Highly pathogenic avian influenza viruses (HPAIV) emerge from low pathogenic avian influenza viruses (LPAIV) through the introduction of basic amino acids at the hemagglutinin (HA) cleavage site. Following viral evolution, the newly formed HPAIV likely represents a minority variant within the index host, predominantly infected with the LPAIV precursor. Using reverse-genetics engineered H5N8 viruses differing solely at the HA cleavage, we tested the hypothesis that the interaction between the minority HPAIV and the majority LPAIV could modulate the risk of HPAIV emergence and that the nature of the interaction could depend on the host species. In chickens, we observed that the H5N8 LP increased H5N8 HP replication and pathogenesis. By contrast, the H5N8 LP antagonized H5N8 HP replication and pathogenesis in ducks. Ducks mounted a more potent antiviral innate immune response than chickens against the H5N8 LP , which correlated with H5N8 HP inhibition. These data provide experimental evidence that HPAIV may be more likely to emerge in chickens than in ducks and underscore the importance of within-host viral variants interactions in viral evolution. IMPORTANCE Highly pathogenic avian influenza viruses represent a threat to poultry production systems and to human health because of their impact on food security and because of their zoonotic potential. It is therefore crucial to better understand how these viruses emerge. Using a within-host competition model between highly and low pathogenic avian influenza viruses, we provide evidence that highly pathogenic avian influenza viruses could be more likely to emerge in chickens than in ducks. These results have important implications for highly pathogenic avian influenza virus emergence prevention and they underscore the importance of within-host viral variants interactions in virus evolution.

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