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Doctoral thesis, 2011

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

Munir, Muhammad

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

Keywords

avian influenzavirus; avian influenza; interferons; alleles; genetic variation; immunology; pathogenicity; minks

Published in

Acta Universitatis Agriculturae Sueciae
2011, number: 2011:100
ISBN: 978-91-576-7644-3
Publisher: Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences

Authors' information

Munir, Muhammad
Swedish University of Agricultural Sciences, Department of Biomedical Science and Veterinary Public Health

UKÄ Subject classification

Pathobiology

URI (permanent link to this page)

https://res.slu.se/id/publ/35713