Interferon Signaling in Chickens Plays a Crucial Role in Inhibiting Influenza Replication in DF1 Cells

Influenza A viruses (IAV) pose a constant threat to human and poultry health. Of particular interest are the infections caused by highly pathogenic avian influenza (HPAI) viruses, such as H5N1, which cause significant production issues. In response to influenza infection, cells activate immune mechanisms that lead to increased interferon (IFN) production. To investigate how alterations in the interferon signaling pathway affect the cellular response to infection in the chicken, we used CRISPR/Cas9 to generate a chicken cell line that lacks a functional the type I interferon receptor (IFNAR1). We then assessed viral infections with the WSN strain of influenza. Cells lacking a functional IFNAR1 receptor showed reduced expression of the interferon stimulated genes (ISG) such as Protein Kinase R (PKR) and Myxovirus resistance (Mx) and were more susceptible to viral infection with WSN. We further investigated the role or IFNAR1 on low pathogenicity avian influenza (LPAI) strains (H7N9) and a HPAI strain (H5N1). Intriguingly, Ifnar−/− cells appeared more resistant than WT cells when infected with HPAI virus, potentially indicating a different interaction between H5N1 and the IFN signaling pathway. Our findings support that ChIFNAR1 is a key component of the chicken IFN signaling pathway and these data add contributions to the field of host-avian pathogen interaction and innate immunity in chickens.

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TRIM35 mediates protection against influenza infection by activating TRAF3 and degrading viral PB2

Protein & Cell ◽

10.1007/s13238-020-00734-6 ◽

2020 ◽

Vol 11 (12) ◽

pp. 894-914

Author(s):

Nan Sun ◽

Li Jiang ◽

Miaomiao Ye ◽

Yihan Wang ◽

Guangwen Wang ◽

...

Keyword(s):

Influenza A ◽

Viral Infections ◽

Influenza Infection ◽

Type I ◽

Subsequent Formation ◽

Antiviral Immune Response ◽

Signaling Complex ◽

Deficient Mice

AbstractTripartite motif (TRIM) family proteins are important effectors of innate immunity against viral infections. Here we identified TRIM35 as a regulator of TRAF3 activation. Deficiency in or inhibition of TRIM35 suppressed the production of type I interferon (IFN) in response to viral infection. Trim35-deficient mice were more susceptible to influenza A virus (IAV) infection than were wild-type mice. TRIM35 promoted the RIG-I-mediated signaling by catalyzing Lys63-linked polyubiquitination of TRAF3 and the subsequent formation of a signaling complex with VISA and TBK1. IAV PB2 polymerase countered the innate antiviral immune response by impeding the Lys63-linked polyubiquitination and activation of TRAF3. TRIM35 mediated Lys48-linked polyubiquitination and proteasomal degradation of IAV PB2, thereby antagonizing its suppression of TRAF3 activation. Our in vitro and in vivo findings thus reveal novel roles of TRIM35, through catalyzing Lys63- or Lys48-linked polyubiquitination, in RIG-I antiviral immunity and mechanism of defense against IAV infection.

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Deletion of Irf3 and Irf7 Genes in Mice Results in Altered Interferon Pathway Activation and Granulocyte-Dominated Inflammatory Responses to Influenza A Infection

Journal of Innate Immunity ◽

10.1159/000450705 ◽

2016 ◽

Vol 9 (2) ◽

pp. 145-161 ◽

Cited By ~ 20

Author(s):

Bastian Hatesuer ◽

Hang Thi Thu Hoang ◽

Peggy Riese ◽

Stephanie Trittel ◽

Ingo Gerhauser ◽

...

Keyword(s):

Immune Response ◽

Knockout Mice ◽

Influenza A ◽

Viral Infections ◽

Inflammatory Responses ◽

Adaptive Immune Response ◽

Strong Increase ◽

Type I ◽

Influenza A Viruses ◽

Double Knockout

The interferon (IFN) pathway plays an essential role in the innate immune response following viral infections and subsequent shaping of adaptive immunity. Infections with influenza A viruses (IAV) activate the IFN pathway after the recognition of pathogen-specific molecular patterns by respective pattern recognition receptors. The IFN regulatory factors IRF3 and IRF7 are key players in the regulation of type I and III IFN genes. In this study, we analyzed the role of IRF3 and IRF7 for the host response to IAV infections in Irf3-/-, Irf7-/-, and Irf3-/-Irf7-/- knockout mice. While the absence of IRF3 had only a moderate impact on IFN expression, deletion of IRF7 completely abolished IFNα production after infection. In contrast, lack of both IRF3 and IRF7 resulted in the absence of both IFNα and IFNβ after IAV infection. In addition, IAV infection of double knockout mice resulted in a strong increase of mortality associated with a massive influx of granulocytes in the lung and reduced activation of the adaptive immune response.

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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

Journal of General Virology ◽

10.1099/vir.0.031716-0 ◽

2011 ◽

Vol 92 (9) ◽

pp. 2111-2121 ◽

Cited By ~ 18

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.

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The perpetuation of orthomyxoviruses and paramyxoviruses in Canadian waterfowl

Canadian Journal of Microbiology ◽

10.1139/m80-108 ◽

1980 ◽

Vol 26 (5) ◽

pp. 622-629 ◽

Cited By ~ 203

Author(s):

V. S. Hinshaw ◽

R. G. Webster ◽

B. Turner

Keyword(s):

Avian Influenza ◽

Influenza A ◽

Influenza Infection ◽

Longitudinal Survey ◽

Influenza Viruses ◽

Antigenic Drift ◽

Influenza A Viruses ◽

High Incidence ◽

Low Incidence ◽

Apparently Healthy

A longitudinal survey of viruses in feral ducks from 1976 to 1978 in the Vermillion area of Alberta, Canada, has shown that influenza A viruses and paramyxoviruses are present year after year in these apparently healthy ducks. Influenza viruses were isolated most frequently each year from mallards, pintails, and blue-winged teals, but were not restricted to these species. During the 3-year survey, 1262 influenza viruses were isolated from 4827 ducks, revealing the high incidence of influenza infection, a finding which contrasts with the very low incidence found in ducks during migration through Tennessee.Many different influenza A viruses were detected in the ducks, including 27 different combinations of hemagglutinin and neuraminidase subtypes. These viruses encompass all but one of the known hemagglutinin and neuraminidase subtypes. The virus subtypes in the ducks varied from year to year; however, 6 of these 27 subtypes were present every year. The predominant subtype changed from Hav7Neq2 in 1976–1977 to Hav6N2 in 1978. Antigenic comparisons of current and previous Hav6 viruses isolated from ducks, turkeys, and a shearwater showed that antigenic drift occurs in avian influenza viruses.Paramyxoviruses occur in the Canadian ducks at a much lower frequency than influenza viruses; in 3 years, 69 paramyxoviruses were isolated and included two types: lentogenic NDV and Duck/Mississippi/75.These longitudinal studies indicate that the feral ducks in the study area of Canada are a perpetual reservoir of diverse influenza A viruses and paramyxoviruses.

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Identification of key mRNAs and lncRNAs involved in the effects of anti-TWEAK on Osteosarcoma

Current Bioinformatics ◽

10.2174/1574893615999200626191405 ◽

2020 ◽

Vol 15 ◽

Author(s):

Mingxuan Yang ◽

Liangtao Zhao ◽

Xuchang Hu ◽

Haijun Feng ◽

Xuewen Kang

Keyword(s):

Dna Replication ◽

Signaling Pathway ◽

Bioinformatics Analysis ◽

Mapk Signaling ◽

Migration And Invasion ◽

Type I ◽

Interferon Signaling ◽

Nf Kappa B ◽

Ppi Networks ◽

Coexpression Networks

Background: Osteosarcoma (OS) is one of the most common primary malignant bone tumors in teenagers. Emerging studies demonstrated TWEAK and Fn14 were involved in regulating cancer cell differentiation, proliferation, apoptosis, migration and invasion. Objective: The present study identified differently expressed mRNAs and lncRNAs after anti-TWEAK treatment in OS cells using GSE41828. Methods: We identified 922 up-regulated mRNAs, 863 downregulated mRNAs, 29 up-regulated lncRNAs, and 58 down-regulated lncRNAs after anti-TWEAK treatment in OS cells. By constructing PPI networks, we identified several key proteins involved in anti-TWEAK treatment in OS cells, including MYC, IL6, CD44, ITGAM, STAT1, CCL5, FN1, PTEN, SPP1, TOP2A, and NCAM1. By constructing lncRNAs coexpression networks, we identified several key lncRNAs, including LINC00623, LINC00944, PSMB8-AS1, LOC101929787. Result: Bioinformatics analysis revealed DEGs after anti-TWEAK treatment in OS were involved in regulating type I interferon signaling pathway, immune response related pathways, telomere organization, chromatin silencing at rDNA, and DNA replication. Bioinformatics analysis revealed differently expressed lncRNAs after antiTWEAK treatment in OS were related to telomere organization, protein heterotetramerization, DNA replication, response to hypoxia, TNF signaling pathway, PI3K-Akt signaling pathway, Focal adhesion, Apoptosis, NF-kappa B signaling pathway, MAPK signaling pathway, FoxO signaling pathway. Conclusion: : This study provided useful information for understanding the mechanisms of TWEAK underlying OS progression and identifying novel therapeutic markers for OS.

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Development and application of a real-time RT-PCR assay to rapidly detect H2 subtype avian influenza A viruses

Journal of Veterinary Diagnostic Investigation ◽

10.1177/1040638721994810 ◽

2021 ◽

pp. 104063872199481

Author(s):

Yixin Xiao ◽

Fan Yang ◽

Fumin Liu ◽

Hangping Yao ◽

Nanping Wu ◽

...

Keyword(s):

Avian Influenza ◽

Real Time ◽

Influenza A ◽

Minor Groove Binder ◽

Rt Pcr ◽

Influenza A Viruses ◽

Pcr Assay ◽

Infectious Dose ◽

The Matrix ◽

Taqman Minor Groove Binder

The H2 subtypes of avian influenza A viruses (avian IAVs) have been circulating in poultry, and they have the potential to infect humans. Therefore, establishing a method to quickly detect this subtype is pivotal. We developed a TaqMan minor groove binder real-time RT-PCR assay that involved probes and primers based on conserved sequences of the matrix and hemagglutinin genes. The detection limit of this assay was as low as one 50% egg infectious dose (EID50)/mL per reaction. This assay is specific, sensitive, and rapid for detecting avian IAV H2 subtypes.

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CD169/SIGLEC1 is expressed on circulating monocytes in COVID-19 and expression levels are associated with disease severity

Infection ◽

10.1007/s15010-021-01606-9 ◽

2021 ◽

Author(s):

Jan-Moritz Doehn ◽

Christoph Tabeling ◽

Robert Biesen ◽

Jacopo Saccomanno ◽

Elena Madlung ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Disease Severity ◽

Clinical Studies ◽

Viral Infections ◽

Severe Disease ◽

Type I Interferons ◽

Type I ◽

Interferon Signaling ◽

Expression Levels

AbstractCoronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Type I interferons are important in the defense of viral infections. Recently, neutralizing IgG auto-antibodies against type I interferons were found in patients with severe COVID-19 infection. Here, we analyzed expression of CD169/SIGLEC1, a well described downstream molecule in interferon signaling, and found increased monocytic CD169/SIGLEC1 expression levels in patients with mild, acute COVID-19, compared to patients with severe disease. We recommend further clinical studies to evaluate the value of CD169/SIGLEC1 expression in patients with COVID-19 with or without auto-antibodies against type I interferons.

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