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Title: Structural basis for distinctive receptor tropism of emerging paramyxoviruses
Author: Stelfox, Alice
ISNI:       0000 0004 8507 1878
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2020
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A diverse array of viruses capable of infecting both humans and animals constitute the family Paramyxoviridae (Amarasinghe et al. 2019; Fields, Knipe, and Howley 2013). Concerns regarding the interspecies transmission potential paramyxoviruses harboured by wildlife reservoirs has motivated subsequent concerted viral surveillance efforts (Thibault et al. 2017; Drexler et al. 2012). Our understanding of many of these newly identified paramyxoviruses is primarily limited to genome information. However, paramyxovirus genomic variation (Holmes 2010; Kitchen, Shackelton, and Holmes 2011) often impedes our ability to predict the pathogenic potential based upon study of primary sequence alone. Therefore, investigations into paramyxovirus structure and function are vital to elucidating the potential biomedical and economic significance of emerging paramyxoviruses (Zeltina, Bowden, and Lee 2016). The six-bladed beta-propeller receptor binding protein (RBP), responsible for host-cell attachment and initiation of the merger of the viral and host-cell membranes (Fields, Knipe, and Howley 2013; Jardetzky and Lamb 2014), is therefore a central determinant of tissue and species tropism (Thibault et al. 2017; Zeltina, Bowden, and Lee 2016). Characterisation of the RBP, through structural and functional approaches, may enhance our ability to rationalise host range and interspecies transmission potential. Within this thesis, the RBPs of a number of recently classified paramyxoviruses are studied: the pararubulavirus, Sosuga virus (SosV); the narmoviruses, Mossman virus (MosV) and Nariva virus (NarV); the jeilongviruses, J virus (JPV) and Beilong virus (BeiV) (Amarasinghe et al. 2019). In my investigations, I found that despite presentation of several stringently conserved residues associated with sialic acid activity, SosV-RBP lacks hemadsorption and neuraminidase functionality characteristic of closely related viruses, such as mumps virus (Kubota et al. 2016). Absence of activity is rationalised by discovery of structural rearrangements to key sialic acid interacting motifs, such as the triarginyl motif (Crennell et al. 2000), and physicochemical incompatibilities at the expected receptor binding site. Similarly, the jeilongviruses do not display hemadsorption or neuraminidase activity despite conservation of canonical sialic acid interacting motifs. Structural study of the jeilongviral RBPs, has enabled the characterisation of a C-terminal extension that forms a domain that occludes the putative sialic acid site. This provides evidence that jeilongviral RBPs employ an auto-inhibitory function analogous to the one utilised by the RBP of Newcastle disease virus Ulster strain (Yuan et al. 2012). Contrasting pararubulavirus and jeilongvirus RBPs, narmovirus RBPs display a beta-propeller architecture that bears no motifs associated with known modes of paramyxovirus-receptor interactions. However, sequence conservation mapping reveals an extended footprint of elevated amino acid sequence identity on the surface of the protein. Efforts utilising site-directed mutagenesis are being implemented to explore the importance of this region in dictating cell interactions. Through crystallographic and biochemical analysis, this thesis provides a structure-based rationale for understanding the pathobiological independence of the newly defined (Amarasinghe et al. 2019) Pararubula-, Narmo-, and Jeilongviruses from other genera within the Paramyxoviridae, where the RBPs of these viruses are likely incapable of utilising currently known modes of paramyxoviral host-cell recognition. Finally, this work provides a platform to identify the receptors utilised by these unique groups of pathogens.
Supervisor: Bowden, Thomas Sponsor: Nuffield Department of Medicine ; Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: virology ; molecular biology ; structural biology ; Biochemistry