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.

Publications

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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