Effects of NS1 variants of H5N1 influenza virus on interferon induction, TNFα response and p53 activity

Li, Weizhong; Wang, Gefei; Zhang, Heng; Xu, Gang; Zhang, Dangui; Zeng, Jun; Chen, Xiaoxuan; Xu, Yanxuan; Cui, You‐Hong; Li, Kangsheng

doi:10.1038/cmi.2010.6

Cited by 28 publications

(22 citation statements)

References 37 publications

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“…As a consequence, all domains of NS1 might be affected, and it is therefore difficult to determine the contribution of changes in individual domains to the reduced virulence of the reassortants from this study. Known substitutions that could alter pathogenicity (7,19,20,21,26,31) were not found except for a difference between the NS1-reassortants and the backbone strain at position 103, which is related to binding of CPSF30 (17). Compared to the backbone strain, our reassortants have a Y103F mutation, which could not be related to altered IFN b production in A549 or MiLu cells (25).…”

contrasting

confidence: 48%

Contribution of the NS1 Gene of H7 Avian Influenza Virus Strains to Pathogenicity in Chickens

et al. 2013

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Using reverse genetics (rg), we generated two reassortant viruses carrying the NS1 gene of two closely related HPAIV and LPAIV H7N1 variants (designated rgH7N7 HP(HPNS1) and rgH7N7 HP(LPNS1), respectively) in the backbone of the HP H7N7 strain A/Chicken/Netherlands/621557/03 (rgH7N7 HP). Comparison of these reassortants allowed us to determine the effect of amino acid differences in the nuclear export and nucleolar localization sequences of NS1 on pathogenesis in chickens. Compared to rgH7N7 HP(LPNS1), a delay in weight gain and an increase in mortality were observed for rgH7N7 HP(HPNS1). Furthermore, an increase in viral load in brains, lungs, and cloacal swabs, as well as an increased induction of mRNA for type I interferons and pro-inflammatory cytokines in brains, were observed for rgH7N7 HP(HPNS1). Comparison of rgH7N7 HP(LPNS1) with the backbone strain rgH7N7 HP allowed us to examine differences in pathogenesis due to differences in NS1 alleles. rgH7N7 HP, which contained allele A of NS1 showed a higher in vitro replication rate and proved to be more virulent than the isogenic virus carrying allele B of NS1(rgH7N7 HP(LPNS1)). In addition, higher virus accumulation in the lungs and brains, and an increased induction of host gene responses, especially in the brains, were found for rgH7N7 HP compared to rgH7N7 HP(LPNS1). No large differences were observed in type I interferon expression in the lungs of chickens infected with any of the viruses, suggesting that differences in virulence due to differences in NS1 could be related to differences in the induction of pro-inflammatory cytokines in vital organs such as the brains.

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confidence: 48%

Contribution of the NS1 Gene of H7 Avian Influenza Virus Strains to Pathogenicity in Chickens

et al. 2013

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“…The relative contribution of the alternative NF-κB signaling pathway for IAV replication is not clear, as infection with IAV strains expressing the NS1 protein only modestly activates the noncanonical NF-κB pathway [99,100]. The NS1 protein was also reported to impair the transcriptional activity of other transcription factors such as p53 [101] and immune-proteasome pathways [98]. It is conceivable that NS1 will affect more cellular signaling steps, as interactome screens have shown numerous cellular binding partners for this viral protein including members of the PI3K (phosphoinositide-3-kinase) and AKT signaling pathways [102,103].…”

Section: Iav Inhibiting Functions Of Nf-κbmentioning

confidence: 99%

The intricate interplay between RNA viruses and NF-κB

Schmitz

Kracht

Saul

2014

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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RNA viruses have rapidly evolving genomes which often allow cross-species transmission and frequently generate new virus variants with altered pathogenic properties. Therefore infections by RNA viruses are a major threat to human health. The infected host cell detects trace amounts of viral RNA and the last years have revealed common principles in the biochemical mechanisms leading to signal amplification that is required for mounting of a powerful antiviral response. Components of the RNA sensing and signaling machinery such as RIG-I-like proteins, MAVS and the inflammasome inducibly form large oligomers or even fibers that exhibit hallmarks of prions. Following a nucleation event triggered by detection of viral RNA, these energetically favorable and irreversible polymerization events trigger signaling cascades leading to the induction of antiviral and inflammatory responses, mediated by interferon and NF-κB pathways. Viruses have evolved sophisticated strategies to manipulate these host cell signaling pathways in order to ensure their replication. We will discuss at the examples of influenza and HTLV-1 viruses how a fascinating diversity of biochemical mechanisms is employed by viral proteins to control the NF-κB pathway at all levels.

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“…An artificially generated virus lacking amino acids 80–84 also acquired the NS1-92E mutation [41], and viruses possessing both markers have been detected in nature, suggesting a functional relationship between these mutations. Further studies have shown that the five-amino acid deletion affects TNF-α levels, whereas the amino acid at position 92 regulates the level of IFN induction [42]. …”

Section: The Viral Interferon Antagonist Ns1 Proteinmentioning

confidence: 99%

H5N1 Influenza Virulence, Pathogenicity and Transmissibility: What do We Know?

Neumann

2015

Future Virol.

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Highly pathogenic influenza viruses of the H5N1 subtype have infected more than 600 people since 1997, resulting in the deaths of approximately 60% of those infected. Multiple studies have established the viral hemagglutinin (HA) surface glycoprotein as the major determinant of H5N1 virulence. HA mediates host-specific virus binding to cells, and mutations that allow efficient binding to viral receptors on mammalian cells are critical (although not sufficient) for H5N1 transmissibility among mammals. The viral polymerase PB2 protein is also a critical virulence determinant, and adaptive mutations in this protein are crucial for efficient H5N1 virus replication in mammals. Additionally, viral proteins (such as NS1 and PB1-F2) with roles in innate immune responses also affect the virulence of highly pathogenic H5N1 viruses.

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Effects of NS1 variants of H5N1 influenza virus on interferon induction, TNFα response and p53 activity

Cited by 28 publications

References 37 publications

Contribution of the NS1 Gene of H7 Avian Influenza Virus Strains to Pathogenicity in Chickens

Contribution of the NS1 Gene of H7 Avian Influenza Virus Strains to Pathogenicity in Chickens

The intricate interplay between RNA viruses and NF-κB

H5N1 Influenza Virulence, Pathogenicity and Transmissibility: What do We Know?

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