Structural studies on human viruses
Lead Research Organisation:
MRC Virology Unit
Abstract
We wish to understand the structure of virus particles and how they interact with the host cell. This can provide insights into many aspects of virus biology and may suggest strategies for treatment. The Main virus being studied is herpes simplex virus, which is a widespread human pathogen causing a variety of diseases. Virus replication and virus particle formation are complex, multistage processes involving the products of many virus genes. We are determining the three-dimensional structure of the virus at different stages during its replication cycle to determine how the structure dictates the assembly and disassembly mechanisms. This is combined with molecular genetic analyses to produce a comprehensive description of the processes leading to the formation and spread of infectious virus particles.
Technical Summary
Knowledge of the structure of viruses and how they interact with the host cell is essential for understanding the processes involved in infection. Virion morphogenesis is a central feature of the life cycle of any virus, and a clear understanding of this process can provide insights into many aspects of virus biology and may suggest possible strategies for therapeutic intervention. We use both structural and molecular genetic approaches to visualise virus particles at various stages during their replication. Herpesviruses are double-stranded DNA viruses that have icosahedral particles, which are surrounded by asymmetrical protein and lipid layers. The structure of the herpesvirus virion is under study in collaboration with Wah Chiu at Baylor College of Medicine in Houston. Both icosahedral and tomographic reconstruction approaches are being used to visualise the symmetrical and asymmetrical features of the particles and uncover the relationships between them. These structural analyses are now being extended to examine virus particles interacting with host cells at various stages during entry, transport and assembly. In parallel studies, the functions of virus structural proteins and their interactions with cellular proteins during the processes of infection and virus maturation, are being examined by molecular biological, mutational and microscopical studies. These complementary analyses are helping to produce fundamental insights into the processes controlling the assembly and dis-assembly, of these important pathogens.
Organisations
- MRC Virology Unit, United Kingdom (Lead Research Organisation)
- Aarhus University, Denmark (Collaboration)
- University of Cologne, Germany (Collaboration)
- University of Sydney, Australia (Collaboration)
- National Center for Scientific Research (Centre National de la Recherche Scientifique CNRS) (Collaboration)
- Baylor College of Medicine, United States (Collaboration)
Publications

Adamson WE
(2006)
Mutational analysis of the herpes simplex virus triplex protein VP19C.
in Journal of virology


Baker ML
(2006)
Ab initio modeling of the herpesvirus VP26 core domain assessed by CryoEM density.
in PLoS computational biology

Bhella D
(2002)
Significant differences in nucleocapsid morphology within the Paramyxoviridae.
in The Journal of general virology

Bhella D
(2004)
The structure of echovirus type 12 bound to a two-domain fragment of its cellular attachment protein decay-accelerating factor (CD 55).
in The Journal of biological chemistry

Bhella D
(2002)
Significant differences in nucleocapsid morphology within the Paramyxoviridae
in JOURNAL OF GENERAL VIROLOGY

Bhella D
(2008)
Structural insights into calicivirus attachment and uncoating.
in Journal of virology

Bhella D
(2000)
Cryomicroscopy of human cytomegalovirus virions reveals more densely packed genomic DNA than in herpes simplex virus type 1.
in Journal of molecular biology

Bhella D
(2004)
Conformational flexibility in recombinant measles virus nucleocapsids visualised by cryo-negative stain electron microscopy and real-space helical reconstruction.
in Journal of molecular biology

Cao Z
(2007)
Reconstitution of the mitochondrial PrxIII antioxidant defence pathway: general properties and factors affecting PrxIII activity and oligomeric state.
in Journal of molecular biology
Description | Member of STFC advisory panel on Life Sciences and Soft Materials |
Geographic Reach | National |
Policy Influence Type | Participation in a advisory committee |
Description | Cryo-Electron Microscopy Equipment Grants |
Amount | £4,400,000 (GBP) |
Funding ID | MC_PC_17135 |
Organisation | LifeArc |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 06/2017 |
End | 07/2022 |
Description | Structural characterisation of the calicivirus entry pathway and its role in defining virulence |
Amount | £848,091 (GBP) |
Funding ID | BB/T002239/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2020 |
End | 12/2022 |
Title | Cell line |
Description | Cell lines expressing HSV structural proteins for complementing virus mutants. |
Type Of Material | Cell line |
Year Produced | 2007 |
Provided To Others? | Yes |
Impact | The cell lines have allowed study of essential stages in virus life cycles leading to publications. |
Title | Cryo-EM |
Description | A cryo-EM facility was set up comprising JEOL 2200 EM, high pressure freezing and freeze substitution. |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2007 |
Provided To Others? | Yes |
Impact | This facility is the first of its type in Scotland and has been used to produce several strucures for Unit members and collaborators that have been published. |
Title | Establishment of Scottish Centre for Macromolecular Imaging |
Description | I led a successful consortium bid to secure funding for a Scottish national centre for CryoEM. Based in the University of Glasgow, this centre will provide access to world-class structural biology resources for Scotland and Northern England. |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | The centre is still in the installation phase. |
Title | Calicivirus VP2 forms a portal to mediate endosome escape |
Description | CryoEM datasets of calicivirus bound to receptor fragment Two datasets: https://dx.doi.org/10.6019/EMPIAR-10192 https://dx.doi.org/10.6019/EMPIAR-10193 |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | Publication Calicivirus VP2 forms a portal-like assembly following receptor engagement Conley MJ, McElwee M, Azmi LB, Gabrielsen M, Byron O, Goodfellow IG, Bhella D Nature (2019) PMID: 30626974 The paper was widely reported and featured in the Diamond Light Source annual review 2019/20 https://www.diamond.ac.uk/docroot/flippingbooks/DiamondAnnualReview2020/86-87/ Reporting: http://www.virology.ws/2019/02/14/a-portal-for-rna-exit/ http://www.microbe.tv/twiv/twiv-534/?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+twivmp3+%28This+Week+in+Virology+-+MP3+Edition%29 https://www.thetimes.co.uk/article/scientists-find-a-new-way-to-fight-norovirus-qbtttd5gz?fbclid=IwAR3RdkImGrc36czjK9-2wgzcO_IYNU_rcDfHPgrY4qnec-RIvLMsNwut7o4 https://www.heraldscotland.com/news/17346160.glasgow-norovirus-breakthrough-lead-first-treatment-winter-vomiting-bug/ |
URL | https://dx.doi.org/10.6019/EMPIAR-10193 |
Title | Structure of the herpes-simplex virus portal-vertex |
Description | Cryo-EM dataset of herpes simplex virions. |
Type Of Material | Database/Collection of data |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | Publication Structure of the herpes simplex virus portal-vertex McElwee M, Vijayakrishnan S, Rixon FJ, Bhella D PLoS Biol. 16 (2018) PMID: 29924793 Reported on Diamond light source webpage https://www.diamond.ac.uk/Science/Research/Highlights/2018/State-of-the-art-imaging-and-image-processing-offer-new-insights-into-Herpes-simplex-virus-.html |
URL | https://dx.doi.org/10.6019/EMPIAR-10189 |
Description | Herpes simplex virus entry |
Organisation | University of Cologne |
Department | Center for Biochemistry |
Country | Germany |
Sector | Academic/University |
PI Contribution | Collection of data, preparation of manuscripts, planning and direction of research. |
Collaborator Contribution | Collection of data, preparation of manuscripts, planning and direction of research. |
Impact | Publication of a manuscript in 2011 |
Start Year | 2008 |
Description | Herpes simplex virus transport mechanisms |
Organisation | National Center for Scientific Research (Centre National de la Recherche Scientifique CNRS) |
Department | Laboratory of Molecular and Structural Virology CNRS |
Country | France |
Sector | Academic/University |
PI Contribution | Development and preparation of reagents, collection of data, preparation of manuscripts, planning and direction of research. |
Collaborator Contribution | Development and preparation of reagents, collection of data, preparation of manuscripts, planning and direction of research. |
Impact | Publication of four manuscripts in 2010, 2011 and 2012 |
Start Year | 2009 |
Description | Non-adaptive immune resposes to HSV |
Organisation | Aarhus University |
Department | Department of Biomedicine |
Country | Denmark |
Sector | Academic/University |
PI Contribution | Collection of data, preparation of manuscripts, planning and direction of research. |
Collaborator Contribution | Collection of data, preparation of manuscripts, planning and direction of research. |
Impact | Publication of a manuscripts in 2011 and 2012 |
Start Year | 2010 |
Description | Structural studies on herpes simplex virus |
Organisation | Baylor College of Medicine |
Department | National Institute for Macromolecular Imaging |
Country | United States |
Sector | Academic/University |
PI Contribution | Development and preparation of reagents, collection of data, preparation of manuscripts, planning and direction of research. |
Collaborator Contribution | Development and preparation of reagents, collection of data, preparation of manuscripts, planning and direction of research. Travel and accommodation costs for collaborative visits (3 working visits to Houston in 2010, 1 in 2011, 2 in 2012). |
Impact | Publication of 18 papers and 3 reviews/chapters, 5 since 2006. Disciplines involved cover molecular virology and structural biology. |
Description | herpes simplex virus neuronal transport |
Organisation | University of Sydney |
Department | Westmead Milleninium institute |
Country | Australia |
Sector | Academic/University |
PI Contribution | Development and preparation of reagents, preparation of manuscripts. |
Collaborator Contribution | Development and preparation of reagents, collection of data, preparation of manuscripts, planning and direction of research. |
Impact | Publication of three papers, two since 2006 |
Description | 04/08/2021 - CVR Flagship Video - Massimo Palmarini |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | CVR's main publicity video used for all advertising of CVR things |
Year(s) Of Engagement Activity | 2021 |
URL | https://youtu.be/KEzc2RDGThA |
Description | STEM in The Gorbals @GorbalsSTEM |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | STEM in the Gorbals is a a series of innovative and ambitious public engagement and science communication events in conjunction with local primary schools in the Gorbals, promoting STEM engagement in areas with traditionally low participation. |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.gla.ac.uk/explore/scienceconnects/news/headline_593073_en.html |