Molecular evolution of equine influenza virus non-structural protein 1

Chauché, Caroline Marie (2018) Molecular evolution of equine influenza virus non-structural protein 1. PhD thesis, University of Glasgow.

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Abstract

Influenza A viruses (IAVs) are common infections of certain avian reservoir species, and they periodically transfer to mammalian hosts. These cross-species jumps are usually associated with sporadic outbreaks, and on rare occasions lead to the establishment of a lineage in the new host species. The immune pressure exerted by the new host on the emergent virus forces it to evolve and adopt strategies to evade immunity in order to survive in nature. Understanding the biological mechanisms that allow successful inter-species transmission and adaptation to mammals is crucial to develop the theoretical tools required to predict and/or control emergence of new viruses in humans and animals. H3N8 equine influenza virus (EIV) represents an interesting model to study the dynamic of within-host variation of an avian-origin IAV. Indeed, this virus has emerged from birds in 1963 and has circulated in horse populations for more than fifty years despite the availability of vaccines. Evidence of evolution of EIV virulence factor non-structural protein 1 (NS1) also exists. NS1 is the main viral antagonist of the host interferon (IFN) response, and it relies on different strategies for overcoming these responses, which varies depending on the viral strain. While some NS1 proteins effectively block the induction of IFN and IFN stimulated genes (ISGs), others block general gene expression at a post-transcriptional level, and therefore reduce the synthesis of IFN and ISGs indirectly. Importantly, little is known about the contribution of these NS1 functions to EIV infection phenotype and adaptation to horses.
In this work, we characterised NS1 proteins spanning the entire EIV lineage and showed that NS1s from different time periods after EIV emergence counteract the IFN response using different and mutually exclusive mechanisms. While EIVs circulating in the early 1960s blocked general gene expression by a NS1-mediated blockade of the cleavage and polyadenylation specificity factor 30 (CPSF30), NS1s from contemporary EIVs specifically inhibit the induction of ISGs by interfering with the JAK/STAT pathway. These contrasting anti-IFN strategies are associated with two mutations that appeared sequentially during EIV evolution, E186K substitution and C-terminal truncation. These changes in NS1 allowed contemporary EIVs to replicate in the presence of high levels of IFN. The results shown here with EIV indicate that the interplay between virus evolution and immune evasion plays a key role in IAV mammalian adaptation.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Influenza virus, NS1 protein, viral evolution, virus-host interactions.
Subjects: Q Science > QR Microbiology > QR180 Immunology
Q Science > QR Microbiology > QR355 Virology
S Agriculture > SF Animal culture > SF600 Veterinary Medicine
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation > Centre for Virus Research
Supervisor's Name: Murcia, Dr. Pablo and Marshall, Dr. John
Date of Award: 2018
Depositing User: Miss Caroline Marie / CC CHAUCHE
Unique ID: glathesis:2018-8877
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 26 Apr 2018 08:43
Last Modified: 14 May 2018 10:41
URI: http://theses.gla.ac.uk/id/eprint/8877
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