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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Abstract
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 | ||||||||||||
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Title: | Immuno-regulatory dynamics of non-structural protein 1 of avian influenza A viruses | ||||||||||||
Subtitle: | IFN-β, NF-κB and AP-1 perspectives | ||||||||||||
Series/Journal: | Acta Universitatis Agriculturae Sueciae (1652-6880) | ||||||||||||
Year of publishing : | 2011 | ||||||||||||
Number: | 2011:100 | ||||||||||||
Number of Pages: | 97 | ||||||||||||
Papers/manuscripts: |
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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 | ||||||||||||
ISSN: | 1652-6880 | ||||||||||||
Language: | English | ||||||||||||
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 | ||||||||||||
URN:NBN: | urn:nbn:se:slu:epsilon-e-286 | ||||||||||||
Permanent URL: | http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-e-286 | ||||||||||||
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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