Structural studies of human viruses and host interactions
Lead Research Organisation:
MRC Virology Unit
Abstract
Virus particles are dynamic structures that replicate inside the cells of their host. We wish to understand their structure and how they interact with the cell. This can provide insights into many aspects of virus biology and may suggest strategies for treatment. The viruses being studied include measles virus, viruses that cause respiratory illnesses (influenza virus and respiratory syncytial virus), viruses that cause liver disease (Hepatitis B and C viruses) and viruses related to those that cause winter vomiting disease (Caliciviruses and Norovirus). We are determining the three-dimensional structures of the viruses at different stages during their replication and as they interact with host molecules to determine how their form relates to their function. We are also interested in the use of viruses to prevent disease through development of novel vaccines.
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 cryogenic electron microscopy and tomography to visualise virus particles at various stages during their replication. Five virus families that cause disease in humans are currently under study; caliciviruses and hepaciviruses (positive strand RNA viruses), orthomyxoviruses and paramyxoviruses (negative strand RNA viruses) and hepadnaviruses (double-stranded DNA viruses).
Paramyxoviruses (measles and respiratory syncytial virus) have characteristic, helical ribonucleoprotein (RNP) cores that act as the templates for genome replication and expression. We are interested in investigating these structures as they undergo their different biological processes: mRNA and genomic RNA synthesis and packaging during virion morphogenesis. Virus assembly in Orthomyxoviruses (Influenza viruses) and Paramyxoviruses leads to both filamentous and spherical forms of enveloped virions. Cryotomography approaches are being used to analyse asymmetric entities such as these, as well as virus-infected cells. In particular we are interested in applying 3D imaging to the study of more biologically relevant cell systems that mimic the host tissue in which infection takes place.
Caliciviruses, hepaciviruses and hepadnaviruses all have icosahedral particles, which in hepaci and hepadnaviruses are surrounded by a lipid envelope. Icosahedral reconstruction is being used to investigate the structure of hepadnavirus capsids that have been modified to display foreign epitopes for use both as a vaccine candidate and also to solve the structure of the inserted polypeptides. We are studying virus entry and tropism in calicivirus and hepaciviruses by investigating the interaction between particles and specific host molecules: cellular receptors, neutralising antibodies. Knowledge of these interactions can inform vaccine design and development of antiviral therapies.
Paramyxoviruses (measles and respiratory syncytial virus) have characteristic, helical ribonucleoprotein (RNP) cores that act as the templates for genome replication and expression. We are interested in investigating these structures as they undergo their different biological processes: mRNA and genomic RNA synthesis and packaging during virion morphogenesis. Virus assembly in Orthomyxoviruses (Influenza viruses) and Paramyxoviruses leads to both filamentous and spherical forms of enveloped virions. Cryotomography approaches are being used to analyse asymmetric entities such as these, as well as virus-infected cells. In particular we are interested in applying 3D imaging to the study of more biologically relevant cell systems that mimic the host tissue in which infection takes place.
Caliciviruses, hepaciviruses and hepadnaviruses all have icosahedral particles, which in hepaci and hepadnaviruses are surrounded by a lipid envelope. Icosahedral reconstruction is being used to investigate the structure of hepadnavirus capsids that have been modified to display foreign epitopes for use both as a vaccine candidate and also to solve the structure of the inserted polypeptides. We are studying virus entry and tropism in calicivirus and hepaciviruses by investigating the interaction between particles and specific host molecules: cellular receptors, neutralising antibodies. Knowledge of these interactions can inform vaccine design and development of antiviral therapies.
Organisations
- MRC Virology Unit, United Kingdom (Lead Research Organisation)
- European Molecular Biology Laboratory (Collaboration)
- University of Cambridge (Collaboration)
- University of Glasgow, United Kingdom (Collaboration)
- Cornell University (Collaboration)
- Pasteur Institute, Paris (Collaboration)
- Boston University, United States (Collaboration)
- Medical Research Council (Collaboration)
People |
ORCID iD |
David Bhella (Principal Investigator) |
Publications

Bakker SE
(2013)
The respiratory syncytial virus nucleoprotein-RNA complex forms a left-handed helical nucleocapsid.
in The Journal of general virology

Bakker, S.E.
(2013)
Pretty Nasty, symmetry in virus architecture.
in The Biochemist


Bhella D
(2019)
Overcoming the Challenges of Symmetry Reveals New Insights into Herpesvirus Biology.
in Cell

Bhella D
(2015)
The role of cellular adhesion molecules in virus attachment and entry.
in Philosophical transactions of the Royal Society of London. Series B, Biological sciences

Conley M
(2017)
Vesivirus 2117 capsids more closely resemble sapovirus and lagovirus particles than other known vesivirus structures.
in The Journal of general virology

Dietrich I
(2011)
Feline tetherin efficiently restricts release of feline immunodeficiency virus but not spreading of infection.
in Journal of virology


McElwee M
(2018)
Structure of the herpes simplex virus portal-vertex
in PLOS Biology

Neuman BW
(2011)
A structural analysis of M protein in coronavirus assembly and morphology.
in Journal of structural biology
Title | Continuum - Movie for display in a planetarium |
Description | Following an artist in residence scheme, Newcastle artist Paul Grimmer created a movie inspired by viral symmetry for display in a digital planetarium |
Type Of Art | Film/Video/Animation |
Year Produced | 2009 |
Impact | Screened at British Association of Planetaria conference, launched at the Centre for Life. http://www.paulgrimmer.co.uk/2010/05/continuum-press-release.html |
URL | http://youtu.be/Z2J6ZwTkAas |
Title | Molecular Machines |
Description | Molecular Machines was a touring exhibition of artworks based on images from virology research |
Type Of Art | Artwork |
Year Produced | 2007 |
Impact | Considerable news reporting in print and broadcast media. |
URL | http://www.molecularmachines.org.uk |
Title | Movie - Engineering adenoviruses for gene therapy |
Description | A short CGI animation of adenovirus interaction with coagulation factor X |
Type Of Art | Film/Video/Animation |
Year Produced | 2012 |
Impact | 13,000 views on YouTube |
URL | http://youtu.be/ONPShTMR6To |
Description | RCUK CATALYSTS panel membership |
Geographic Reach | National |
Policy Influence Type | Participation in advisory committee |
Description | BBSRC WestBio DTG |
Amount | £101,704 (GBP) |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2013 |
End | 09/2017 |
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 | R01 |
Amount | $190,789 (USD) |
Funding ID | 1R01AI113321 |
Organisation | National Institutes of Health (NIH) |
Sector | Public |
Country | United States |
Start | 06/2014 |
End | 07/2018 |
Description | Response Mode |
Amount | £751,764 (GBP) |
Funding ID | MR/M000451/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 11/2014 |
End | 11/2017 |
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 | 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 | Calicivirus attachment and entry |
Organisation | Cornell University |
Department | Baker Institute for Animal Health |
Country | United States |
Sector | Academic/University |
PI Contribution | We solved the structure of Calicivirus bound to it's receptor and identified structural changes that occur - possibly a first step towards uncoating |
Collaborator Contribution | Provided purified virus and protein |
Impact | Papers in Journal of Virology Pubmed 18550656, 21865392, 27902397 |
Start Year | 2007 |
Description | Calicivirus attachment and entry |
Organisation | European Molecular Biology Laboratory |
Department | European Molecular Biology Laboratory Heidelberg |
Country | Germany |
Sector | Academic/University |
PI Contribution | We solved the structure of Calicivirus bound to it's receptor and identified structural changes that occur - possibly a first step towards uncoating |
Collaborator Contribution | Provided purified virus and protein |
Impact | Papers in Journal of Virology Pubmed 18550656, 21865392, 27902397 |
Start Year | 2007 |
Description | Calicivirus attachment and entry |
Organisation | University of Cambridge |
Department | Virology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We solved the structure of Calicivirus bound to it's receptor and identified structural changes that occur - possibly a first step towards uncoating |
Collaborator Contribution | Provided purified virus and protein |
Impact | Papers in Journal of Virology Pubmed 18550656, 21865392, 27902397 |
Start Year | 2007 |
Description | Focussed Ion Beam Milling of Virus infected cells |
Organisation | University of Glasgow |
Department | Physics and Astronomy Department |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Conceived and performed experiments to explore the use of FIB-SEM to image the virus infected cell, secured funding to add cryo-capability to instrument, collaborated on design of bespoke components to allow transfer of frozen hydrated cells into the FIB-SEM microscope. |
Collaborator Contribution | Worked to help us develop this technology using their microscope, providing access to the instrument. |
Impact | Preliminary data collected. Work is multidisciplinary - with Physics dept, Grant funding secured (MR/M000451/1) |
Start Year | 2012 |
Description | Structural studies of Adenovirus Factor X interaction |
Organisation | University of Glasgow |
Department | BHF Glasgow Cardiovascular Research Centre |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We solved the structure of Adenovirus bound to Factor X, an interaction which directs the virus to the liver. Based on our low-resolution EM structure we constructed an atomic resolution model which guided mutagenesis studies to ablate binding. |
Collaborator Contribution | Several papers in high impact journals |
Impact | Papers in Cell, Blood and Molecular therapy Pubmed 19603000, 19429866, 18267072 |
Description | Structure of Paramyxovirus Nucleocapsids |
Organisation | Pasteur Institute, Paris |
Department | Department of Virology |
Country | France |
Sector | Academic/University |
PI Contribution | Provided low-resolution structural data to facilitate solution of X-ray structure of Respiratory Syncytial Virus. Solved structure of helical assembly to allow modelling of authentic nucleocapsid structure. |
Collaborator Contribution | Publication of high impact papers |
Impact | Paper in Science (Pubmed 19965480) Paper in Journal of General Virology (Pubmed 23677789) |
Start Year | 2006 |
Description | Structure of RSV RNA dependent RNA polymerase |
Organisation | Boston University |
Country | United States |
Sector | Academic/University |
PI Contribution | Structural analysis of Respiratory Syncytial Virus RdRp complexes |
Collaborator Contribution | Providing protein preparations and expertise |
Impact | Secured grant funding (MR/M000451/1) |
Start Year | 2012 |
Description | Structure of Respiratory Syncytial Virus |
Organisation | Medical Research Council (MRC) |
Department | MRC Laboratory of Molecular Biology (LMB) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Designed experiments, collected and processed preliminary data. |
Collaborator Contribution | Use of LMB cryomicroscope to collect higher quality EM data on RSV. Training in helical reconstruction provided by Dr Jude Short of LMB to support our project. |
Impact | Data collection ongoing Secured grant funding (MR/M000451/1 |
Start Year | 2013 |
Description | Article in SGM magazine microbiology today |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | I wrote an article describing outreach activities conducted by the CVR in partnership with Glasgow Science Centre. This year I was nominated for the Peter Wildy prize for microbiology communication by the SGM virus group. I think this article prompted that nomination. |
Year(s) Of Engagement Activity | 2012 |
Description | Article in The Biochemist |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | We wrote an article on virus structure and symmetry for a special edition of 'The Biochemist'. The magazine of the biochemical society. Read by members of the society |
Year(s) Of Engagement Activity | 2013 |
Description | Glasgow Science Festival |
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 | ~40 students attended a workshop where they investigated a fictional virus outbreak by molecular biology and diagnostic methods The workshop received excellent evaluation feedback from participants |
Year(s) Of Engagement Activity | 2011,2012,2013,2014 |
Description | Meet the expert |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | We regularly conduct drop in meet the expert activities at Glasgow Science Centre, involving a range of activities: Build a virus - young children make models of viruses, Strawberry DNA children and adults extract DNA from fruit, Diagnosing viral diarrhoea - children and adults perform a mocked up latex agglutination test, Virus culture - children and adults look at (formaldehyde fixed) viral cultures. In November 2014, I will be running a microscopy themed school activity in partnership with the Scottish Microscopy Group. These activities achieve a high degree engagement depth with detailed one-to-one discussions. |
Year(s) Of Engagement Activity | 2010,2011,2012,2013,2014 |