An NS-segment exonic splicing enhancer regulates influenza A virus replication in mammalian cells

Huang, Xiaofeng; Zheng, Min; Wang, Pui; Mok, Bobo Wing-Yee; Liu, Siwen; Lau, Siu-Ying; Chen, Pin; Liu, Yen Chin; Hong-lian, Liu; Chen, Yixin; Song, Wenjun; Yuen, Kwok‐Yung; Chen, Honglin

doi:10.1038/ncomms14751

Cited by 57 publications

(72 citation statements)

References 60 publications

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“…Hence, the orchestrated synthesis of the viral proteome appears to be critically important for permissive infection. This supports the emerging view that modulation of viral protein synthesis underpins host adaptation 63 . Specifically, we find that the strain-specific differences in M1 protein synthesis critically depend on a conserved cis-regulatory element, which controls M-segment mRNA splicing.…”

Section: Discussionsupporting

confidence: 84%

The dynamic proteome of influenza A virus infection identifies M segment splicing as a host range determinant

Bogdanow

Eichelbaum

Sadewasser

et al. 2018

Preprint

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A century ago, influenza A virus (IAV) infection caused the 1918 flu pandemic and killed an estimated 20-40 million people. Pandemic IAV outbreaks occur when strains from animal reservoirs acquire the ability to infect and spread among humans. The molecular details of this species barrier are incompletely understood. We combined metabolic pulse labeling and quantitative shotgun proteomics to globally monitor protein synthesis upon infection of human cells with a human-and a bird-adapted IAV strain. While production of host proteins was remarkably similar, we observed striking differences in the kinetics of viral protein synthesis over the course of infection. Most importantly, the matrix protein M1 was inefficiently produced by the bird-adapted strain at later stages. We show that impaired production of M1 from bird-adapted strains is caused by increased splicing of the M segment RNA to alternative isoforms. Experiments with reporter constructs and recombinant influenza viruses revealed that strain-specific M segment splicing is controlled by the 3' splice site and functionally important for permissive infection.Independent in silico evidence shows that avian-adapted M segments have evolved different conserved RNA structure features than human-adapted sequences. Thus, our data identifies M segment RNA splicing as a viral determinant of host range.3

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Section: Discussionsupporting

confidence: 84%

The dynamic proteome of influenza A virus infection identifies M segment splicing as a host range determinant

Bogdanow

Eichelbaum

Sadewasser

et al. 2018

Preprint

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“…Although no specific clinical sign and/or increase in the severity of respiratory disease in pigs was associated with infections with SwD group strains, it would be informative to further investigate potential group-specific phenotypic and/or functional characteristics. RNA secondary structure modification could indeed impact the splicing of NS mRNAs and subsequently regulate the expression of NS1 and NS2, two proteins that have important functions in the inhibition of host antiviral gene expression and/or in viral replication (37,49,50).…”

Section: Discussionmentioning

confidence: 99%

Spatiotemporal Distribution and Evolution of the A/H1N1 2009 Pandemic Influenza Virus in Pigs in France from 2009 to 2017: Identification of a Potential Swine-Specific Lineage

Chastagner

Hervé

Bonin

et al. 2018

J Virol

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The H1N1 influenza virus responsible for the most recent pandemic in 2009 (H1N1pdm) has spread to swine populations worldwide while it replaced the previous seasonal H1N1 virus in humans. In France, surveillance of swine influenza A viruses in pig herds with respiratory outbreaks led to the detection of 44 H1N1pdm strains between 2009 and 2017, regardless of the season, and findings were not correlated with pig density. From these isolates, 17 whole-genome sequences were obtained, as were 6 additional hemagglutinin (HA)/neuraminidase (NA) sequences, in order to perform spatial and temporal analyses of genetic diversity and to compare evolutionary patterns of H1N1pdm in pigs to patterns for human strains. Following mutation accumulation and fixation over time, phylogenetic analyses revealed for the first time the divergence of a swine-specific genogroup within the H1N1pdm lineage. The divergence is thought to have occurred around 2011, although this was demonstrated only through strains isolated in 2015 to 2016 in the southern half of France. To date, these H1N1pdm swine strains have not been related to any increased virulence in swine herds and have not exhibited any antigenic drift compared to seasonal human strains. However, further monitoring is encouraged, as diverging evolutionary patterns in these two species, i.e., swine and humans, may lead to the emergence of viruses with a potentially higher risk to both animal and human health.IMPORTANCE Pigs are a “mixing vessel” for influenza A viruses (IAVs) because of their ability to be infected by avian and human IAVs and their propensity to facilitate viral genomic reassortment events. Also, as IAVs may evolve differently in swine and humans, pigs can become a reservoir for old human strains against which the human population has become immunologically naive. Thus, viruses from the novel swine-specific H1N1pdm genogroup may continue to diverge from seasonal H1N1pdm strains and/or from other H1N1pdm viruses infecting pigs and lead to the emergence of viruses that would not be covered by human vaccines and/or swine vaccines based on antigens closely related to the original H1N1pdm virus. This discovery confirms the importance of encouraging swine IAV monitoring because H1N1pdm swine viruses could carry an increased risk to both human and swine health in the future as a whole H1N1pdm virus or gene provider in subsequent reassortant viruses.

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“…Recently, Huang et al. 's () study also has suggested that HP viruses originated mainly from the LP viruses of the Yangtze River Delta region that originated from a Wave 3‐like viruses and then obtained the four‐basic amino acid insertion in the Pearl River Delta. Guided by the ideas of Jin et al.…”

Section: Resultsmentioning

confidence: 99%

“…LP H7N9 viruses evolved into HP viruses by insertion of multibasic amino acids into the cleavage site (Huang et al., ), this multibasic cleavage site (MBCS) insertion can promote rapid cracking of HA0 (Munster et al., ), and high cleavability of the haemagglutinin glycoprotein was a necessary condition for lethal infection (Hatta, Gao, Halfmann, & Kawaoka, ). It has been confirmed that the basic amino acids around the HA cleavage site are the main factors determining the virulence of the influenza virus in chickens (Senne et al., ; Webster & Rott, ).…”

Section: Discussionmentioning

confidence: 99%

A comprehensive comparison of the fifth‐wave highly pathogenic and low‐pathogenic H7N9 avian influenza viruses reveals potential threat posed by both types of viruses in mammals

Liu

et al. 2018

Transbound Emerg Dis

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Before 2013, zoonotic influenza infections were dominated by H5N1 viruses in China. However, the emergence of the H7N9 viruses in early 2013 changed this dominance greatly, and more than 1,600 laboratory-confirmed human cases of H7N9 infections have been reported since then. To understand the underlying mechanism of the emergence of the fifth epidemic wave that shows an unexpected sharp increase, we systematically investigated the biological characteristics of the highly pathogenic (HP) and low-pathogenic (LP) H7N9 AIVs during this period. We first systematically analysed the haemagglutination assay gene of all the isolates available from the website and found that the HP and LP viruses differed a little in the well-established receptor binding sites and in other potentially important sites. Phylogenetic analysis showed that both the HP and LP viruses belong to the branch of the Yangtze River Delta, whereas they diverged to different small branches. To further compare the biological variations in the HP and LP viruses, we selected six HP and six LP strains for in-depth analysis, including receptor binding characteristics, thermal stability, viral replication and virulence in mice. The three major findings of this study were as follows: (a) Other potential site/sites may affect the receptor binding property of the H7N9 viruses; (b) the HP viruses displayed a higher thermostability than did the LP viruses, quite consistent with the epidemiological data during the summer period; and (c) one-third of the HP viruses were moderately pathogenic in mice, whereas all the LP viruses were nonpathogenic in this animal model. However, the LP viruses replicated more efficiently in the mouse lung and can spread to the extrarespiratory organs (spleen, kidney and brain). Taken together, our results suggest that both the HP and LP H7N9 viruses can pose a potential threat to public health, highlighting the importance of the continual surveillance of the H7N9 AIVs.

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An NS-segment exonic splicing enhancer regulates influenza A virus replication in mammalian cells

Cited by 57 publications

References 60 publications

The dynamic proteome of influenza A virus infection identifies M segment splicing as a host range determinant

The dynamic proteome of influenza A virus infection identifies M segment splicing as a host range determinant

Spatiotemporal Distribution and Evolution of the A/H1N1 2009 Pandemic Influenza Virus in Pigs in France from 2009 to 2017: Identification of a Potential Swine-Specific Lineage

A comprehensive comparison of the fifth‐wave highly pathogenic and low‐pathogenic H7N9 avian influenza viruses reveals potential threat posed by both types of viruses in mammals

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