The matrix gene of pdm/09 H1N1 contributes to the pathogenicity and transmissibility of SIV in mammals

Zhu, Junda; Jiang, Zhimin; Liu, Jinhua

doi:10.1016/j.vetmic.2021.109039

Cited by 12 publications

(7 citation statements)

References 51 publications

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“…Others have shown the origin of viral segments such as PB1 and NS1 genes may also contribute to swine influenza strain virulence and disease (59, 60). Recently, a reverse genetics approach was used to compare influenza virus replication and disease in BALB/c mice, comparing a Eurasian-origin M gene with the pdmM gene in an Asian-origin H1N1 virus background (61). The pdmM gene conferred increased virus titers, mortality, and disease, supporting our hypothesis and observations, although the Eurasian M gene is distinct from the classical swM gene we assessed here (16).…”

Section: Discussionmentioning

confidence: 99%

Swine influenza A virus isolates containing the pandemic H1N1 origin matrix gene elicit greater disease in the murine model

Curran,

Griffin,

Ferreri

et al. 2023

Preprint

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Since the 1990’s, endemic North American swine influenza A viruses (swFLUAV) contained an internal gene segment constellation referred to as the triple reassortment internal gene (TRIG) cassette. In 2009, the H1N1 pandemic (pdmH1N1) virus spilled back into swine, but did not become endemic. However, the pdmH1N1 did contribute the matrix gene segment (pdmM) to the swFLUAVs circulating in the pig population; which replaced the classical swine matrix gene (swM) found in the TRIG cassette, suggesting that the pdmM has a fitness benefit. Others have shown that swFLUAV containing the pdmM have greater neuraminidase activity and transmission efficiency compared to viruses containing the swM gene segment. We hypothesized that the matrix gene could also affect disease and utilized two infection models, resistant BALB/c and susceptible DBA/2 mice, to assess swFLUAV pathogenicity. We infected BALB/c and DBA/2 mice with a panel of H1 and H3 swFLUAVs containing the swM or pdmM gene and measured lung virus titers, morbidity, mortality, and lung histopathology. H1 influenza strains containing the pdmM gene caused greater morbidity and mortality in both resistant and susceptible murine strains, while H3 swFLUAVs caused no clinical disease. However, both H1 and H3 swFLUAVs containing the pdmM replicated to higher viral titers in the lungs and pdmM containing H1 viruses induced greater histological changes compared to swM H1 viruses. While the surface glycoproteins contribute to swFLUAV pathogenicity, and other genes also influence disease, these data suggest that the origin of the matrix gene also contributes to pathogenicity of swFLUAV viruses in mice.

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Section: Discussionmentioning

confidence: 99%

Swine influenza A virus isolates containing the pandemic H1N1 origin matrix gene elicit greater disease in the murine model

Curran,

Griffin,

Ferreri

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Some studies have reported that the M1 protein plays an important role in determining the morphology of influenza viruses, and morphology can affect viral transmission and virulence ( 47 – 50 ). Therefore, we investigated whether the D30N and A215T mutations affect the morphology of the DKFJ/01 virus.…”

Section: Resultsmentioning

confidence: 99%

SUMOylation of Matrix Protein M1 and Filamentous Morphology Collectively Contribute to the Replication and Virulence of Highly Pathogenic H5N1 Avian Influenza Viruses in Mammals

Guo

Chen

et al. 2022

J Virol

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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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“…Others have shown the origin of viral segments such as PB1 and NS1 genes may also contribute to swine influenza strain virulence and disease ( 58 , 59 ). Recently, a reverse genetic approach was used to compare influenza virus replication and disease in BALB/c mice, comparing a Eurasian-origin M gene with the pdmM gene in an Asian-origin H1N1 virus background ( 60 ). The pdmM gene conferred increased virus titers, mortality, and disease, supporting our hypothesis and observations, although the Eurasian M gene is distinct from the classical swM gene we assessed here ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

Swine influenza A virus isolates containing the pandemic H1N1 origin matrix gene elicit greater disease in the murine model

Curran,

Griffin,

Ferreri

et al. 2024

Microbiol Spectr

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Since the 1990s, endemic North American swine influenza A viruses (swFLUAVs) contained an internal gene segment constellation, the triple reassortment internal gene (TRIG) cassette. In 2009, the H1N1 pandemic (pdmH1N1) virus spilled back into swine but did not become endemic. However, the pdmH1N1 contributed the matrix gene (pdmM) to the swFLUAVs circulating in the pig population, which replaced the classical swine matrix gene (swM) found in the TRIG cassette, suggesting the pdmM has a fitness benefit. Others have shown that swFLUAVs containing the pdmM have greater transmission efficiency compared to viruses containing the swM gene segment. We hypothesized that the matrix (M) gene could also affect disease and utilized two infection models, resistant BALB/c and susceptible DBA/2 mice, to assess pathogenicity. We infected BALB/c and DBA/2 mice with H1 and H3 swFLUAVs containing the swM or pdmM and measured lung virus titers, morbidity, mortality, and lung histopathology. H1 influenza strains containing the pdmM gene caused greater morbidity and mortality in resistant and susceptible murine strains, while H3 swFLUAVs caused no clinical disease. However, both H1 and H3 swFLUAVs containing the pdmM replicated to higher viral titers in the lungs and pdmM containing H1 viruses induced greater histological changes compared to swM H1 viruses. While the surface glycoproteins and other gene segments may contribute to swFLUAV pathogenicity in mice, these data suggest that the origin of the matrix gene also contributes to pathogenicity of swFLUAV in mice, although we must be cautious in translating these conclusions to their natural host, swine. IMPORTANCE The 2009 pandemic H1N1 virus rapidly spilled back into North American swine, reassorting with the already genetically diverse swFLUAVs. Notably, the M gene segment quickly replaced the classical M gene segment, suggesting a fitness benefit. Here, using two murine models of infection, we demonstrate that swFLUAV isolates containing the pandemic H1N1 origin M gene caused increased disease compared to isolates containing the classical swine M gene. These results suggest that, in addition to other influenza virus gene segments, the swFLUAV M gene segment contributes to pathogenesis in mammals.

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The matrix gene of pdm/09 H1N1 contributes to the pathogenicity and transmissibility of SIV in mammals

Cited by 12 publications

References 51 publications

Swine influenza A virus isolates containing the pandemic H1N1 origin matrix gene elicit greater disease in the murine model

Swine influenza A virus isolates containing the pandemic H1N1 origin matrix gene elicit greater disease in the murine model

SUMOylation of Matrix Protein M1 and Filamentous Morphology Collectively Contribute to the Replication and Virulence of Highly Pathogenic H5N1 Avian Influenza Viruses in Mammals

Swine influenza A virus isolates containing the pandemic H1N1 origin matrix gene elicit greater disease in the murine model

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