Molecular biology of foot-and-mouth disease virus: entry, replication and assembly
Lead Research Organisation:
The Pirbright Institute
Department Name: UNLISTED
Abstract
This project will carry out research on the fundamental molecular mechanisms of
picornavirus entry, replication and assembly with a long term view of using improved mechanistic understanding to provide novel targets/strategies for disease control. This project underpins the
externally funded research of the Picornavirus Molecular Biology Group.
picornavirus entry, replication and assembly with a long term view of using improved mechanistic understanding to provide novel targets/strategies for disease control. This project underpins the
externally funded research of the Picornavirus Molecular Biology Group.
Organisations
- The Pirbright Institute, United Kingdom (Lead Research Organisation)
- University of Oxford, United Kingdom (Collaboration)
- University of Edinburgh, United Kingdom (Collaboration)
- University of Leuven (Collaboration)
- Imperial College London, United Kingdom (Collaboration)
- University of Glasgow, United Kingdom (Collaboration)
- Medical Research Council (Collaboration)
- University of York, United Kingdom (Collaboration)
- Technical University of Denmark (Collaboration)
- University of Dundee, United Kingdom (Collaboration)
- University of Leeds, United Kingdom (Collaboration)
- University of St Andrews, United Kingdom (Collaboration)
- Harvard University (Collaboration)
- Polytechnic University of Valencia (Collaboration)
- Sanofi (Collaboration)
People |
ORCID iD |
| Tobias Tuthill (Principal Investigator) |
Publications
Groppelli E
(2017)
Picornavirus RNA is protected from cleavage by ribonuclease during virion uncoating and transfer across cellular and model membranes.
in PLoS pathogens
Guedán A
(2017)
Investigation of the Role of Protein Kinase D in Human Rhinovirus Replication.
in Journal of virology
Herod MR
(2017)
Genetic economy in picornaviruses: Foot-and-mouth disease virus replication exploits alternative precursor cleavage pathways.
in PLoS pathogens
Logan G
(2018)
Deep Sequencing of Foot-and-Mouth Disease Virus Reveals RNA Sequences Involved in Genome Packaging.
in Journal of virology
Malik N
(2017)
Structures of foot and mouth disease virus pentamers: Insight into capsid dissociation and unexpected pentamer reassociation.
in PLoS pathogens
Newman J
(2018)
The Cellular Chaperone Heat Shock Protein 90 Is Required for Foot-and-Mouth Disease Virus Capsid Precursor Processing and Assembly of Capsid Pentamers.
in Journal of virology
Panjwani A
(2016)
The conserved N-terminus of human rhinovirus capsid protein VP4 contains membrane pore-forming activity and is a target for neutralizing antibodies.
in The Journal of general virology
Shimmon G
(2016)
Truncated Bovine Integrin Alpha-v/Beta-6 as a Universal Capture Ligand for FMD Diagnosis.
in PloS one
Swatek KN
(2018)
Irreversible inactivation of ISG15 by a viral leader protease enables alternative infection detection strategies.
in Proceedings of the National Academy of Sciences of the United States of America
| Description | The following key findings from this award have been reported as peer reviewed publications: The capsid protein VP4 of rhinovirus induces membrane permeability by forming a multimeric size selective pore. The structure of Ljungan virus provides insight into genome packaging of this picornavirus. FMDV replicons encoding green fluorescent protein are replication competent. Recombinant truncated Bovine Integrin Alpha-v/Beta-6 can be used as a Universal Capture Ligand for FMD Diagnosis. Determination of the Structure of human Aichi virus and its implications for receptor binding. The conserved N-terminus of human rhinovirus capsid protein VP4 contains membrane pore-forming activity and is a target for neutralizing antibodies. Picornavirus RNA is protected from cleavage by ribonuclease during virion uncoating and transfer across cellular and model membranes. The host cell protein kinase D (PKD) is required for replication of rhinovirus and foot-and-mouth disease virus and represents a novel target for disrupting replication. |
| Exploitation Route | Further funding. New research. Antiviral drugs. New antiviral approaches. Improved vaccines. |
| Sectors | Agriculture, Food and Drink,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
| Description | Further funding. New research. New targets for antiviral drugs. New antiviral approaches. Improved vaccines. |
| First Year Of Impact | 2014 |
| Sector | Agriculture, Food and Drink,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
| Impact Types | Economic |
| Description | BBSRC IAA The Pirbright Institute |
| Amount | £300,000 (GBP) |
| Funding ID | BB/S506680/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 03/2018 |
| End | 03/2021 |
| Description | Institute Strategic Programme Award |
| Amount | £6,175,000 (GBP) |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 04/2017 |
| End | 03/2022 |
| Title | Deep sequencing to identify RNA packaging signals |
| Description | A novel and simple approach to identify predicted RNA secondary structures involved in genome packaging in positive sense RNA viruses (e.g. the picornavirus foot-and-mouth disease virus [FMDV]). By interrogating deep sequencing data generated from both packaged and unpackaged populations of RNA, we have determined multiple regions of the genome with constrained variation in the packaged population. Predicted secondary structures of these regions revealed stem-loops with conservation of structure and a common motif at the loop. Disruption of these features resulted in attenuation of virus growth in cell culture due to a reduction in assembly of mature virions. This study provides evidence for the involvement of predicted RNA structures in picornavirus packaging and offers a readily transferable methodology for identifying packaging requirements in many other viruses. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2017 |
| Provided To Others? | Yes |
| Impact | Impact so far is fundamental knowledge but with several potential avenues for future impact in for example improved vaccines. |
| Description | DTU |
| Organisation | Technical University of Denmark |
| Country | Denmark |
| Sector | Academic/University |
| PI Contribution | Joint PhD studentship |
| Collaborator Contribution | Joint PhD studentship |
| Impact | Joint PhD studentship in progress |
| Start Year | 2016 |
| Description | Dundee |
| Organisation | University of Dundee |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Co-INvestigator on BBSRC sLoLa award |
| Collaborator Contribution | Co-INvestigator on BBSRC sLoLa award |
| Impact | BBSRC sLoLa award ongoing |
| Start Year | 2012 |
| Description | Edinburgh |
| Organisation | University of Edinburgh |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Co-INvestigator on BBSRC sLoLa award |
| Collaborator Contribution | Co-INvestigator on BBSRC sLoLa award |
| Impact | BBSRC sLoLa award ongoing |
| Start Year | 2012 |
| Description | Glasgow DH |
| Organisation | University of Glasgow |
| Department | Institute of Cardiovascular and Medical Sciences |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Joint supervision of PhD student |
| Collaborator Contribution | Joint supervision of PhD student |
| Impact | PhD completed. Papers published or in preparation. |
| Start Year | 2013 |
| Description | HMS |
| Organisation | Harvard University |
| Department | Harvard Medical School |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Collaboration |
| Collaborator Contribution | Collaboration |
| Impact | Collaborative research |
| Description | Imperial |
| Organisation | Imperial College London |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Joint supervision of PhD student |
| Collaborator Contribution | Joint supervision of PhD student |
| Impact | One successful completed PhD student. Papers published or in preparation. Another PhD student in progress. |
| Start Year | 2010 |
| Description | JN - Preparation of capped mesoporpus silica nanoparticles |
| Organisation | Polytechnic University of Valencia |
| Country | Spain |
| Sector | Academic/University |
| PI Contribution | We were involved with testing the nanoparticles once they had been made. We also contributed purified antibody and shipped it to our collaborators for the generation of one type of nanoparticle, which we subsequently tested. We were involved with the intellectual design of experiments |
| Collaborator Contribution | Our partners generated the nanoparticles and shipped them to us for testing. Our partners were also involved with the intellectual design of experiments. |
| Impact | Experimental work performed to investigate the use of mesoporous silica nanoparticles to detect FMDV proteases in clinical samples |
| Start Year | 2016 |
| Description | JS - Production of monoclonal antibodies that recognise FMDV VP4 from mouse spleens |
| Organisation | University of Edinburgh |
| Department | The Roslin Institute |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | VLPs displaying the N-terminal 15 amino acids of FMDV were designed and produced at The Pirbright Institute and then mice were immunised with them. The spleens of the immunised mice were harvested and splenocytes stored. The response to the VP4 sequence was checked by ELISA and the mouse with the best response was selected to send the splenocytes for monoclonal production. |
| Collaborator Contribution | The collaborators took the splenocytes obtained from the mouse experiments and carried out the fusions. They then screened the supernatants for positive wells that detected the VP4 sequence. |
| Impact | Positive wells have been identified indicating some monoclonals that are specific for VP4 have been generated. These will be further screened for ability to recognise virus and to neutralise infection. |
| Start Year | 2017 |
| Description | KU Leuven |
| Organisation | University of Leuven |
| Country | Belgium |
| Sector | Academic/University |
| PI Contribution | collaboration |
| Collaborator Contribution | collaboration |
| Impact | collaboration |
| Start Year | 2012 |
| Description | LMB |
| Organisation | Medical Research Council (MRC) |
| Department | MRC Laboratory of Molecular Biology (LMB) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Collaboration |
| Collaborator Contribution | Collaboration |
| Impact | Collaborative research |
| Start Year | 2016 |
| Description | Leeds FBS |
| Organisation | University of Leeds |
| Department | Leeds Institute of Molecular Medicine |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Research |
| Collaborator Contribution | Research and student supervision |
| Impact | Research |
| Start Year | 2009 |
| Description | Merial |
| Organisation | Sanofi |
| Department | Merial Plc |
| Country | Global |
| Sector | Private |
| PI Contribution | BBSRC Link award |
| Collaborator Contribution | BBSRC Link award |
| Impact | BBSRC Link award in progress |
| Start Year | 2016 |
| Description | Oxford - Strubi |
| Organisation | University of Oxford |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Collaboration on virus structural biology and joint PhD studentship |
| Collaborator Contribution | Collaboration on virus structural biology and joint PhD studentship |
| Impact | Collaboration on virus structural biology has produced a number of novel virus structures and new understanding of virus entry and packaging |
| Start Year | 2008 |
| Description | St Andrews |
| Organisation | University of St Andrews |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Co-investigator on BBSRC sLoLa |
| Collaborator Contribution | Lead-investigator on BBSRC sLoLa |
| Impact | BBSRC sLoLa ongoing |
| Start Year | 2012 |
| Description | York |
| Organisation | University of York |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Collaboration |
| Collaborator Contribution | Collaboration |
| Impact | Collaboration |
| Start Year | 2015 |
| Description | Contributed to FMDV animation for web based outreach. |
| Form Of Engagement Activity | Engagement focused website, blog or social media channel |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | Contributed to FMDV animation for web based outreach. |
| Year(s) Of Engagement Activity | 2016 |
| Description | Diamond (TT) |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | Diamond Light Source Open Day - explaining to general public the importance of structural biology and microscopy for understanding viruses and designing improved vaccines. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Diamond light source open day 7th Nov 2015 |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | Representing The Pirbright Institute at the Diamond light source open day 7th Nov 2015 |
| Year(s) Of Engagement Activity | 2015 |
| Description | Europic Conference (5-8/09/16) |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Europic Conference (5-8/09/16) |
| Year(s) Of Engagement Activity | 2016 |
| Description | FMDV informational video, 15/11/16 |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | FMDV informational video, 15/11/16 |
| Year(s) Of Engagement Activity | 2016 |
| Description | GFRA (TT) |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Global Foot-and-mouth disease Research Alliance (GFRA) meeting, presentation on virus packaging and implications for vaccine production, initiated collaboration discussions between international academic and industry partners. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Guildford college careers fair |
| 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 | manned the stall with exhibits encouraging kids with an interest in science to take up careers in science. |
| Year(s) Of Engagement Activity | 2015 |
| Description | Lecture at the University of Surrey for the MSc Veterinary Programme, 25/10/16 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Postgraduate students |
| Results and Impact | Lectureship at the Univesity of Surrey for the MSc Veterinary Programme, 25/10/16 |
| Year(s) Of Engagement Activity | 2016 |
| Description | Microbiology Society Conference 2016 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Microbiology Society Conference 2016 |
| Year(s) Of Engagement Activity | 2016 |
| Description | Researcher Links Workshop- Istanbul |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Researcher Links Workshop- Istanbul Turkey, May 2015, Food Security: Improving Approaches to Prevent and Control Viral Diseases of Livestock and Poultry- oral presentation. |
| Year(s) Of Engagement Activity | 2015 |
| Description | SGM 2015 Hsp90 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | SGM Birmingham March 28th 2015: Presentation on hsp90 in virus assembly. |
| Year(s) Of Engagement Activity | 2015 |
| Description | STEM Surrey Sports 2015 |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | participation in the Skills Fair at Surrey Sports Park to promote and motivate gifted and talented students towards a career in science |
| Year(s) Of Engagement Activity | 2015 |
| Description | SinoPic TT |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | 'SinoPic': Structural Biology of Picornaviruses meeting in China. Generating interest and collaborations in virus structural biology within China. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Tominscote school careers fair. |
| 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 | Tominscote school careers fair. |
| Year(s) Of Engagement Activity | 2016 |
| Description | University of Leeds postgraduate symposium titled Capsid protein VP4 of foot-and-mouth disease virus as a novel target for disease control. |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Postgraduate students |
| Results and Impact | University of Leeds postgraduate symposium presentation titled Capsid protein VP4 of foot-and-mouth disease virus as a novel target for disease control. |
| Year(s) Of Engagement Activity | 2015 |
| Description | Winston Churchhill Careers Fair, 19/10/16 |
| 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 | Winston Churchhill Careers Fair, 19/10/16 |
| Year(s) Of Engagement Activity | 2016 |