Molecular and biological characterisation of orthobunyaviruses

Slack, Gillian Sinclair (2016) Molecular and biological characterisation of orthobunyaviruses. PhD thesis, University of Glasgow.

Due to Embargo and/or Third Party Copyright restrictions, this thesis is not available in this service.

Abstract

Orthobunyaviruses are the largest genus within the Bunyaviridae family, with over 170
named viruses classified into 18 serogroups (Elliott and Blakqori, 2001; Plyusnin et al.,
2012). Orthobunyaviruses are transmitted by arthropods and have a tripartite negative
sense RNA genome, which encodes 4 structural proteins and 2 non-structural proteins.
The non-structural protein NSs is the primary virulence factor of orthobunyaviruses
and potent antagonist of the type I interferon (IFN) response. However, sequencing
studies have identified pathogenic viruses that lack the NSs protein (Mohamed et al.,
2009; Gauci et al., 2010).

The work presented in this thesis describes the molecular and biological
characterisation of divergent orthobunyaviruses. Data on plaque morphology, growth
kinetics, protein profiles, sensitivity to IFN and activation of the type I IFN system are
presented for viruses in the Anopheles A, Anopheles B, Capim, Gamboa, Guama,
Minatitlan, Nyando, Tete and Turlock serogroups. These are complemented with
complete genome sequencing and phylogenetic analysis. Low activation of IFN by Tete
serogroup viruses, which naturally lack an NSs protein, was also further investigated by
the development of a reverse genetics system for Batama virus (BMAV). Recombinant
viruses with mutations in the virus nucleocapsid protein amino terminus showed higher
activation of type I IFN in vitro and data suggests that low levels of IFN are due to
lower activation rather than active antagonism. The anti-orthobunyavirus activity of
IFN-stimulated genes IFI44, IFITMs and human and ovine BST2 were also studied,
revealing that activity varies not only within the orthobunyavirus genus and virus
serogroups but also within virus species. Furthermore, there was evidence of active
antagonism of the type I IFN response and ISGs by non-NSs viruses.

In summary, the results show that pathogenicity in man and antagonism of the type I
IFN response in vitro cannot be predicted by the presence, or absence, of an NSs ORF.
They also highlight problems in orthobunyavirus classification with discordance
between classical antigen based data and phylogenetic analysis.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Orthobunyaviruses, NSs, phylogeny, classification, type I IFN, Batama virus
Subjects: Q Science > QR Microbiology > QR355 Virology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation > Centre for Virus Research
Supervisor's Name: Jarrett, Prof. Ruth
Date of Award: 2016
Embargo Date: 16 May 2019
Depositing User: Miss Gillian S Slack
Unique ID: glathesis:2016-7303
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 16 May 2016 09:39
Last Modified: 26 May 2016 09:08
URI: http://theses.gla.ac.uk/id/eprint/7303

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