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Immuno-regulatory dynamics of non-structural protein 1 of avian influenza A viruses

IFN-β, NF-κB and AP-1 perspectives

Munir, Muhammad (2011). Immuno-regulatory dynamics of non-structural protein 1 of avian influenza A viruses. Diss. (sammanfattning/summary) Uppsala : Sveriges lantbruksuniv., Acta Universitatis Agriculturae Sueciae, 1652-6880 ; 2011:100
ISBN 978-91-576-7644-3
[Doctoral thesis]

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The type I interferon (IFN-α/β) system represents the first line of defense against influenza A viruses, and is mainly mediated by the interferon regulatory factors 3/7 (IRF3/7), nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1) transcription factors. Therefore, the non-structural protein 1 (NS1) of influenza A viruses has
intrinsic abilities to disarm the host cell IFN system, and as a consequence is deeply connected to influenza virus pathogenicity and virulence. Based on differences in the
amino acid sequence of the NS1 genes, the influenza A viruses are divided into two distinct gene pools, named allele A and B. This division is strictly based on genetic
characterization, and their functional consequences are largely unknown.

The results in this thesis provide novel structural and functional insights, indicating that allele A NS1 proteins of various avian influenza A viruses have a stronger capacity to inhibit the activation of IFN-β production than allele B proteins from corresponding subtypes. This claim was further confirmed by measurement of IFN stimulatory
response element (ISRE) promoter activation, IFN-β mRNA transcription and IFN-β protein expression. Intriguingly, the allele-specific levels of inhibition correlated with
the nature of the disease, where for example allele A influenza virus appeared to be more pathogenic than allele B viruses in minks (Mustela vison). Further investigations
demonstrated that allele B NS1 protein resembles to its IFN antagonistic nature in exerting similar effect in preventing double stranded RNA (dsRNA) induced NF-κB
and AP-1 promoter activation, which subsequently results in an overall inhibition of IFN-β production. In an effort to understand the structural basis of IFN inhibition, it was revealed that inhibitory activities for ISRE, NF-κB and AP-1 promoters and subsequent inhibition of IFN-β were mapped to the C-terminal effector domain of the NS1 protein.

Genetic characterization of a reassortant H9N2 influenza virus revealed that the virus acquired the NS segment from a H5N1 of genotype Z, clade 2.2. Screening the IFN antagonist abilities of both NS1 proteins (H5N1 and H9N2) demonstrated a high degree of functional homology at IRF3, ISRE, NF-κB and AP-1 levels, which resulted in strong inhibition of IFN-β production in cell culture system.

Taken together, these studies expand the information concerning the versatile nature of the NS1 protein and highlight its indispensible role in reassortant influenza A virus pathogenesis

Authors/Creators:Munir, Muhammad
Title:Immuno-regulatory dynamics of non-structural protein 1 of avian influenza A viruses
Subtitle:IFN-β, NF-κB and AP-1 perspectives
Series Name/Journal:Acta Universitatis Agriculturae Sueciae
Year of publishing :2011
Number of Pages:97
I.Zohari, S., Munir, M., Metreveli, G., Belák, S., and Berg, M. (2010). Differences in the ability to suppress interferon beta production between allele A and allele B NS1 proteins from H10 influenza A viruses. Virology Journal 7(1), 376.
II.Munir, M., Zohari, S., Metreveli, G., Baule, C., Belák, S., and Berg, M. (2011). 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 92(9), 2111–2121.
III.Munir, M., Zohari, S., and Berg, M. (2011). Non-structural protein 1 of avian influenza A viruses differentially inhibit NF-κB promoter activation. Virology Journal 8(1), 383.
IV.Munir, M., Zohari, S., Belák, S., and Berg, M. (2011). Double stranded RNA induced activation of activating protein-1 promoter is differentially regulated by non-structural protein 1 of avian influenza A viruses. Viral Immunology (accepted).
V.Munir, M., Zohari, S., Abbas, M., Iqbal, M., Perez, R.D., Belák, B., and Berg, M. (2011). The NS gene segment of H9N2 influenza virus isolated from backyard poultry in Pakistan revealed strong genetic and functional similarities to the NS gene of highly pathogenic H5N1 (manuscript).
Place of Publication:Uppsala
Publisher:Dept. of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences
ISBN for printed version:978-91-576-7644-3
Publication Type:Doctoral thesis
Full Text Status:Public
Agris subject categories.:L Animal production > L73 Animal diseases
Subjects:(A) Swedish standard research categories 2011 > 4 Agricultural Sciences > 403 Veterinary Science > Pathobiology
Agrovoc terms:avian influenzavirus, avian influenza, interferons, alleles, genetic variation, immunology, pathogenicity, minks
Keywords:Allele A and B, avian influenza, IFN-β inhibition, NS1 protein
Permanent URL:
ID Code:8477
Department:(VH) > Dept. of Biomedical Sciences and Veterinary Public Health
External funders:FORMAS
Deposited By: Muhammad Munir
Deposited On:30 Nov 2011 08:19
Metadata Last Modified:02 Dec 2014 10:48

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