scholarly journals Species-Specific Contribution of the Four C-Terminal Amino Acids of Influenza A Virus NS1 Protein to Virulence

2010 ◽  
Vol 84 (13) ◽  
pp. 6733-6747 ◽  
Author(s):  
Sébastien M. Soubies ◽  
Christelle Volmer ◽  
Guillaume Croville ◽  
Josianne Loupias ◽  
Brigitte Peralta ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Virus Replication ◽  
Influenza A ◽  
Large Scale ◽  
Influenza Viruses ◽  
Type I Interferons ◽  
Type I ◽  
Ns1 Protein ◽  
Species Specific ◽  
H7n1 Virus

ABSTRACT Large-scale sequence analyses of influenza viruses revealed that nonstructural 1 (NS1) proteins from avian influenza viruses have a conserved C-terminal ESEV amino acid motif, while NS1 proteins from typical human influenza viruses have a C-terminal RSKV motif. To test the influence of the C-terminal domains of NS1 on the virulence of an avian influenza virus, we generated a wild-type H7N1 virus with an ESEV motif and a mutant virus with an NS1 protein containing a C-terminal RSKV motif by reverse genetics. We compared the phenotypes of these viruses in vitro in human, mouse, and duck cells as well as in vivo in mice and ducks. In human cells, the human C-terminal RSKV domain increased virus replication. In contrast, the avian C-terminal ESEV motif of NS1 increased virulence in mice. We linked this increase in pathogenicity in mice to an increase in virus replication and to a more severe lung inflammation associated with a higher level of production of type I interferons. Interestingly, the human C-terminal RSKV motif of NS1 increased viral replication in ducks. H7N1 virus with a C-terminal RSKV motif replicated to higher levels in ducks and induced higher levels of Mx, a type I interferon-stimulated gene. Thus, we identify the C-terminal domain of NS1 as a species-specific virulence domain.

scholarly journals Alleles A and B of non-structural protein 1 of avian influenza A viruses differentially inhibit beta interferon production in human and mink lung cells

2011 ◽  
Vol 92 (9) ◽  
pp. 2111-2121 ◽  
Author(s):  
Muhammad Munir ◽  
Siamak Zohari ◽  
Giorgi Metreveli ◽  
Claudia Baule ◽  
Sándor Belák ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Influenza A ◽  
Rna Binding ◽  
Type I Interferons ◽  
Lung Cells ◽  
Type I ◽  
Ns1 Protein ◽  
Structural Protein ◽  
Promoter Activation ◽  
Influenza A Viruses

Non-structural protein 1 (NS1) counteracts the production of host type I interferons (IFN-α/β) for the efficient replication and pathogenicity of influenza A viruses. Here, we reveal another dimension of the NS1 protein of avian influenza A viruses in suppressing IFN-β production in cultured cell lines. We found that allele A NS1 proteins of H6N8 and H4N6 have a strong capacity to inhibit the activation of IFN-β production, compared with allele B from corresponding subtypes, as measured by IFN stimulatory response element (ISRE) promoter activation, IFN-β mRNA transcription and IFN-β protein expression. Furthermore, the ability to suppress IFN-β promoter activation was mapped to the C-terminal effector domain (ED), while the RNA-binding domain (RBD) alone was unable to suppress IFN-β promoter activation. Chimeric studies indicated that when the RBD of allele A was fused to the ED of allele B, it was a strong inhibitor of IFN-β promoter activity. This shows that well-matched ED and RBD are crucial for the function of the NS1 protein and that the RBD could be one possible cause for this differential IFN-β inhibition. Notably, mutagenesis studies indicated that the F103Y and Y103F substitutions in alleles A and B, respectively, do not influence the ISRE promoter activation. Apart from dsRNA signalling, differences were observed in the expression pattern of NS1 in transfected human and mink lung cells. This study therefore expands the versatile nature of the NS1 protein in inhibiting IFN responses at multiple levels, by demonstrating for the first time that it occurs in a manner dependent on allele type.

scholarly journals IFITM3 and type I interferons are important for the control of influenza A virus replication in murine macrophages

Virology ◽  
2020 ◽  
Vol 540 ◽  
pp. 17-22 ◽  
Author(s):  
Sarah L. Londrigan ◽  
Linda M. Wakim ◽  
Jeffrey Smith ◽  
Anne J. Haverkate ◽  
Andrew G. Brooks ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Virus Replication ◽  
Influenza A ◽  
Type I Interferons ◽  
Type I ◽  
Murine Macrophages

IFN-κ suppresses the replication of influenza A viruses through the IFNAR-MAPK-Fos-CHD6 axis

2020 ◽  
Vol 13 (626) ◽  
pp. eaaz3381 ◽  
Author(s):  
Yongquan He ◽  
Weihui Fu ◽  
Kangli Cao ◽  
Qian He ◽  
Xiangqing Ding ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Influenza Viruses ◽  
Mitogen Activated Protein Kinase ◽  
Type I Interferons ◽  
Type I ◽  
Influenza A Viruses ◽  
Human Lung Cells ◽  
Avian Influenza A Virus ◽  
Factor C

Type I interferons (IFNs) are the first line of defense against viral infection. Using a mouse model of influenza A virus infection, we found that IFN-κ was one of the earliest responding type I IFNs after infection with H9N2, a low-pathogenic avian influenza A virus, whereas this early induction did not occur upon infection with the epidemic-causing H7N9 virus. IFN-κ efficiently suppressed the replication of various influenza viruses in cultured human lung cells, and chromodomain helicase DNA binding protein 6 (CHD6) was the major effector for the antiviral activity of IFN-κ, but not for that of IFN-α or IFN-β. The induction of CHD6 required both of the type I IFN receptor subunits IFNAR1 and IFNAR2, the mitogen-activated protein kinase (MAPK) p38, and the transcription factor c-Fos but was independent of signal transducer and activator of transcription 1 (STAT1) activity. In addition, we showed that pretreatment with IFN-κ protected mice from lethal influenza viral challenge. Together, our findings identify an IFN-κ–specific pathway that constrains influenza A virus and provide evidence that IFN-κ may have potential as a preventative and therapeutic agent against influenza A virus.

scholarly journals The NS1 protein of influenza A virus suppresses interferon-regulated activation of antigen-presentation and immune-proteasome pathways

2011 ◽  
Vol 92 (9) ◽  
pp. 2093-2104 ◽  
Author(s):  
Jennifer R. Tisoncik ◽  
Rosalind Billharz ◽  
Svetlana Burmakina ◽  
Sarah E. Belisle ◽  
Sean C. Proll ◽  
...  
Keyword(s):  
Gene Expression ◽  
Antigen Presentation ◽  
Influenza A ◽  
H1n1 Influenza ◽  
Influenza Viruses ◽  
Mutant Virus ◽  
Type I ◽  
Ns1 Protein ◽  
Effector Domain ◽  
Regulated Gene Expression

The NS1 protein of influenza virus counters host antiviral defences primarily by antagonizing the type I interferon (IFN) response. Both the N-terminal dsRNA-binding domain and the C-terminal effector domain are required for optimal suppression of host responses during infection. To better understand the regulatory role of the NS1 effector domain, we used an NS1-truncated mutant virus derived from human H1N1 influenza isolate A/Texas/36/91 (Tx/91) and assessed global transcriptional profiles from two independent human lung cell-culture models. Relative to the wild-type Tx/91-induced gene expression, the NS1 mutant virus induced enhanced expression of innate immune genes, specifically NF-κB signalling-pathway genes and IFN-α and -β target genes. We queried an experimentally derived IFN gene set to gauge the proportion of IFN-responsive genes that are suppressed specifically by NS1. We show that the C-terminally truncated NS1 mutant virus is less efficient at suppressing IFN-regulated gene expression associated with activation of antigen-presentation and immune-proteasome pathways. This is the first report integrating genomic analysis from two independent human culture systems, including primary lung cells, using genetically similar H1N1 influenza viruses that differ only in the length of the NS1 protein.

scholarly journals Notorious Novel Avian Influenza Viruses H10N8 and H7N9 in China in 2013 Co-originated from H9N2

2014 ◽  
Author(s):  
Liang Chen ◽  
Feng Zhu ◽  
Chenglong Xiong ◽  
Zhijie Zhang ◽  
Lufang Jiang ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Influenza A ◽  
Phylogenetic Trees ◽  
Large Scale ◽  
Southern China ◽  
Influenza Viruses ◽  
Influenza A Viruses ◽  
Avian Influenza Viruses ◽  
Virus Reassortment ◽  
Epidemiological Characteristics

In 2013, two new avian influenza viruses (AIVs) H7N9 and H10N8 emerged in China caused worldwide concerns. Previous studies have studied their originations independently; this study is the first time to investigate their co-originating characteristics. Gene segments of assorted subtype influenza A viruses, as well as H10N8 and H7N9, were collected from public database. With the help of series software, small and large-scale phylogenetic trees, mean evolutionary rates, and divergence years were obtained successionally. The results demonstrated the two AIVs co-originated from H9N2, and shared a spectrum of mutations in common on many key sites related to pathogenic, tropism and epidemiological characteristics. For a long time, H9N2 viruses had been circulated in eastern and southern China; poultry was the stable and lasting maintenance reservoir. High carrying rate of AIVs H9N2 in poultry had an extremely high risk of co-infections with other influenza viruses, which increased the risk of virus reassortment. It implied that novel AIVs reassortants based on H9N2 might appear and prevail at any time in China; therefore, surveillance of H9N2 AIVs should be given a high priority.

scholarly journals COVID-19: etiology, clinical picture, treatment

2020 ◽  
Vol 10 (3) ◽  
pp. 421-445 ◽  
Author(s):  
M. Yu. Shchelkanov ◽  
L. V. Kolobukhina ◽  
O. A. Burgasova ◽  
I. S. Kruzhkova ◽  
V. V. Maleev
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Clinical Picture ◽  
Influenza A ◽  
Artificial Respiration ◽  
Blood Oxygenation ◽  
Influenza Viruses ◽  
Type I Interferons ◽  
Type I ◽  
Similar System ◽  
History Of

Whereas the XX century marked the history of acute respiratory disease investigation as a period for generating in-depth system of combating influenza viruses (Articulavirales: Orthomyxoviridae, Alpha-/Betainfluenzavirus) (based on environmental and virological monitoring of influenza A virus in its natural reservoir — aquatic and semi-aquatic birds — to supervising epidemic influenza), a similar system is necessary to build up in the XXI century with regard to especially dangerous betacoronaviruses (Nidovirales: Coronaviridae, Betacoronavirus): Severe acute respiratory syndrome-related coronavirus (SARS-CoV) (subgenus Sarbecovirus), Severe acute respiratory syndrome-related coronavirus 2 (SARSCoV-2) (Sarbecovirus), Middle East respiratory syndrome-related coronavirus (MERS-CoV) (Merbecovirus). This became particularly evident after pandemic potential has been revealed in 2020 by the SARS-CoV-2. This review provides an insight into the historic timeline of discovering this virus, its current taxonomy, ecology, virion morphology, life cycle, molecular biology, pathogenesis and clinical picture of the etiologically related COVID-19 (Coronavirus disease 2019) as well as data available in the scientific literature on the anti-SARS-CoV-2-effectiveness of passive immunotherapy and most debated drugs used to treat COVID-19: Chloroquine, Hydroxychloroquine, Nitazoxanide, Ivermectin, Lopinavir and Ritonavir, Camostat mesilate, Remdesivir, Ribavirin, Tocilizumab, Anakinra, corticosteroids, and type I interferons. The pathogenesis of SARS-CoV-2 infection implicates decreased efficacy of artificial respiration, which, in this case might be replaced by more efficient extracorporeal membrane blood oxygenation supplemented with nitrogen oxide and/or Heliox inhalations.

scholarly journals NS1 Proteins of Avian Influenza A Viruses Can Act as Antagonists of the Human Alpha/Beta Interferon Response

2006 ◽  
Vol 81 (5) ◽  
pp. 2318-2327 ◽  
Author(s):  
A. Hayman ◽  
S. Comely ◽  
A. Lackenby ◽  
L. C. S. Hartgroves ◽  
S. Goodbourn ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Mammalian Cells ◽  
Influenza A ◽  
Influenza Viruses ◽  
Type I ◽  
Type I Ifn ◽  
Human Influenza ◽  
Avian Influenza Viruses ◽  
Range Restriction ◽  
Host Range Restriction

ABSTRACT Many viruses, including human influenza A virus, have developed strategies for counteracting the host type I interferon (IFN) response. We have explored whether avian influenza viruses were less capable of combating the type I IFN response in mammalian cells, as this might be a determinant of host range restriction. A panel of avian influenza viruses isolated between 1927 and 1997 was assembled. The selected viruses showed variation in their ability to activate the expression of a reporter gene under the control of the IFN-β promoter and in the levels of IFN induced in mammalian cells. Surprisingly, the avian NS1 proteins expressed alone or in the genetic background of a human influenza virus controlled IFN-β induction in a manner similar to the NS1 protein of human strains. There was no direct correlation between the IFN-β induction and replication of avian influenza viruses in human A549 cells. Nevertheless, human cells deficient in the type I IFN system showed enhanced replication of the avian viruses studied, implying that the human type I IFN response limits avian influenza viruses and can contribute to host range restriction.

scholarly journals The NS1 Protein of a Human Influenza Virus Inhibits Type I Interferon Production and the Induction of Antiviral Responses in Primary Human Dendritic and Respiratory Epithelial Cells

2009 ◽  
Vol 83 (13) ◽  
pp. 6849-6862 ◽  
Author(s):  
Kester Haye ◽  
Svetlana Burmakina ◽  
Thomas Moran ◽  
Adolfo García-Sastre ◽  
Ana Fernandez-Sesma
Keyword(s):  
Influenza Virus ◽  
Epithelial Cells ◽  
Viral Replication ◽  
Influenza A ◽  
Type I Interferon ◽  
Influenza Viruses ◽  
Type I ◽  
Ns1 Protein ◽  
Human Influenza ◽  
Human Influenza Virus

ABSTRACT The NS1 protein of the influenza A virus is a potent virulence factor that inhibits type I interferon (IFN) synthesis, allowing the virus to overcome host defenses and replicate efficiently. However, limited studies have been conducted on NS1 function using human virus strains and primary human cells. We used NS1 truncated mutant influenza viruses derived from the human isolate influenza A/TX/91 (TX WT, where WT is wild type) to study the functions of NS1 in infected primary cells. Infection of primary differentiated human tracheo-bronchial epithelial cells with an NS1 truncated mutant demonstrated limited viral replication and enhanced type I IFN induction. Additionally, human dendritic cells (DCs) infected with human NS1 mutant viruses showed higher levels of activation and stimulated naïve T-cells better than TX WT virus-infected DCs. We also compared infections of DCs with TX WT and our previously characterized laboratory strain A/PR/8/34 (PR8) and its NS1 knockout strain, deltaNS1. TX WT-infected DCs displayed higher viral replication than PR8 but had decreased antiviral gene expression at late time points and reduced naïve T-cell stimulation compared to PR8 infections, suggesting an augmented inhibition of IFN production and human DC activation. Our findings show that human-derived influenza A viruses have a high capacity to inhibit the antiviral state in a human system, and here we have evaluated the possible mechanism of this inhibition. Lastly, C-terminal truncations in the NS1 protein of human influenza virus are sufficient to make the virus attenuated and more immunogenic, supporting its use as a live attenuated influenza vaccine in humans.

scholarly journals The ESEV PDZ-Binding Motif of the Avian Influenza A Virus NS1 Protein Protects Infected Cells from Apoptosis by Directly Targeting Scribble

2010 ◽  
Vol 84 (21) ◽  
pp. 11164-11174 ◽  
Author(s):  
Hongbing Liu ◽  
Lisa Golebiewski ◽  
Eugene C. Dow ◽  
Robert M. Krug ◽  
Ronald T. Javier ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Influenza A ◽  
Molecular Mechanisms ◽  
Consensus Sequence ◽  
Influenza Viruses ◽  
Binding Motif ◽  
Ns1 Protein ◽  
Pdz Proteins ◽  
H5n1 Influenza ◽  
Infected Cells

ABSTRACT The NS1 protein from influenza A viruses contains a four-amino-acid sequence at its carboxyl terminus that is termed the PDZ-binding motif (PBM). The NS1 PBM is predicted to bind to cellular PDZ proteins and functions as a virulence determinant in infected mice. ESEV is the consensus PBM sequence of avian influenza viruses, while RSKV is the consensus sequence of human viruses. Currently circulating highly pathogenic H5N1 influenza viruses encode an NS1 protein with the ESEV PBM. We identified cellular targets of the avian ESEV PBM and identified molecular mechanisms involved in its function. Using glutathione S-transferase (GST) pull-down assays, we found that the ESEV PBM enables NS1 to associate with the PDZ proteins Scribble, Dlg1, MAGI-1, MAGI-2, and MAGI-3. Because Scribble possesses a proapoptotic activity, we investigated the interaction between NS1 and Scribble. The association between NS1 and Scribble is direct and requires the ESEV PBM and two Scribble PDZ domains. We constructed recombinant H3N2 viruses that encode an H6N6 avian virus NS1 protein with either an ESEV or mutant ESEA PBM, allowing an analysis of the ESEV PBM in infections in mammalian cells. The ESEV PBM enhanced viral replication up to 4-fold. In infected cells, NS1 with the ESEV PBM relocalized Scribble into cytoplasmic puncta concentrated in perinuclear regions and also protected cells from apoptosis. In addition, the latter effect was eliminated by small interfering RNA (siRNA)-mediated Scribble depletion. This study shows that one function of the avian ESEV PBM is to reduce apoptosis during infection through disruption of Scribble's proapoptotic function.

scholarly journals PA-X is an avian virulence factor in H9N2 avian influenza virus

2021 ◽  
Vol 102 (3) ◽  
Author(s):  
Anabel L. Clements ◽  
Thomas P. Peacock ◽  
Joshua E. Sealy ◽  
Hui Min Lee ◽  
Saira Hussain ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Virus Replication ◽  
Virulence Factor ◽  
Influenza A ◽  
Influenza Viruses ◽  
Avian Host ◽  
Influenza A Viruses ◽  
In Ovo ◽  
Viral Shedding

Influenza A viruses encode several accessory proteins that have host- and strain-specific effects on virulence and replication. The accessory protein PA-X is expressed due to a ribosomal frameshift during translation of the PA gene. Depending on the particular combination of virus strain and host species, PA-X has been described as either acting to reduce or increase virulence and/or virus replication. In this study, we set out to investigate the role PA-X plays in H9N2 avian influenza viruses, focusing on the natural avian host, chickens. We found that the G1 lineage A/chicken/Pakistan/UDL-01/2008 (H9N2) PA-X induced robust host shutoff in both mammalian and avian cells and increased virus replication in mammalian, but not avian cells. We further showed that PA-X affected embryonic lethality in ovo and led to more rapid viral shedding and widespread organ dissemination in vivo in chickens. Overall, we conclude PA-X may act as a virulence factor for H9N2 viruses in chickens, allowing faster replication and wider organ tropism.

Sign in / Sign up

Export Citation Format

Share Document