Characterization of the non-structural (NSs) protein of tick-borne phleboviruses

Rezelj, Veronica Valentina (2017) Characterization of the non-structural (NSs) protein of tick-borne phleboviruses. PhD thesis, University of Glasgow.

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In recent years, a number of newly discovered tick-borne viruses exhibiting a wide spectrum of diseases in humans have been ascribed to the Phlebovirus genus of the Bunyaviridae family. These viruses have a tripartite RNA genome composed of two negative-sense RNA segments (medium and large) and one ambisense segment (small), which encode four structural proteins and one non-structural protein (NSs). The NSs protein is the major virulence factor of bunyaviruses, and acts as an antagonist of a key component of the first line of defence against viral infections: the interferon (IFN) system (Bridgen et al., 2001; Weber et al., 2002). The work presented herein describes the characterization of tick-borne phlebovirus NSs proteins as IFN antagonists. The development of a reverse genetics system for the apathogenic tick-borne Uukuniemi phlebovirus (UUKV) enabled the recovery of infectious UUKV entirely from cDNA. A recombinant UUKV lacking NSs induced higher amounts of IFN in infected cells compared to wild-type UUKV, suggesting a role of NSs in modulating the IFN response. The weak IFN antagonistic activity of UUKV NSs was evident using transient transfection reporter assays in comparison to the NSs protein of either pathogenic Heartland virus (HRTV) or Severe fever with thrombocytopenia syndrome virus (SFTSV). The sensitivity of UUKV, HRTV and SFTSV to exogenous and virus-induced IFN, as well as their growth kinetics in IFN-competent cells were examined. The molecular mechanisms employed by UUKV, HRTV and SFTSV NSs proteins to evade antiviral immunity were investigated using reporter assays, immunofluorescence, and immunoprecipitation studies. Collectively, these assays showed that UUKV NSs was able to weakly inhibit IFN induction but not IFN signalling, through a novel interaction with MAVS (mitochondrial antiviral signalling protein). On the other hand, HRTV and SFTSV NSs proteins potently inhibited IFN induction through an interaction with TBK1, and type I but not type II IFN signalling via an interaction with STAT2. Finally, the development of a minigenome system for HRTV in conjunction with minigenomes developed for UUKV and SFTSV (Brennan et al., 2015) provided preliminary data to assess possible outcomes of tick-borne phlebovirus reassortment. In summary, the results described in this thesis offer insights into how tick-borne phlebovirus pathogenicity may be linked to the capacity of their NSs proteins to block the innate immune system. The data presented also illustrate the plethora of viral immune evasion strategies utilized by emerging phleboviruses, and provide an insight into the possibility of tick-borne phlebovirus reassortment.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Late Prof Richard M Elliott
Keywords: Phlebovirus, interferon antagonism, reassortment.
Subjects: Q Science > QR Microbiology > QR355 Virology
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Funder's Name: Wellcome Trust (WELLCOME)
Supervisor's Name: Palmarini, Professor Massimo and Brennan, Dr. Benjamin
Date of Award: 2017
Depositing User: Dr Veronica Rezelj
Unique ID: glathesis:2017-8149
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 04 May 2017 09:24
Last Modified: 01 Aug 2022 08:41
Thesis DOI: 10.5525/gla.thesis.8149
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