Testing novel anti-viral strategies in plants
Lead Research Organisation:
University of York
Department Name: Mathematics
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
ssRNA viruses are major pathogens infecting plants and cause severe reductions in crop yields. Viruses are thus a significant threat to efforts to expand and secure the world's food supply. In addition, viruses and virus-like particles (VLPs) are important as potential chimeric vaccines, e.g. against cancer, and as nanoscale containers in applications such as diagnostic imaging and targeted drug delivery. A number of these applications involve VLPs produced in plants - Molecular Pharming. This proposal sets out to test directly a novel anti-viral strategy in plants exploiting fundamental insights into the mechanisms of virus assembly and disassembly. The new concept arises due to our realization that assembly in many ssRNA viruses is mediated by packaging signal (PS)-coat protein interactions. The PSs are regions of the cognate genomes that both bind sequence-specifically to coat proteins and thereby improve the yield, rate and/or fidelity of assembly. These ideas are revising the paradigm in the field which assumes there is no selectivity of genome encapsidation. In addition a second approach towards the same goal arises due to the growing recognition that such viruses extrude their genomes as linear molecules from their capsids as one of the earliest steps in infection. We have shown that for at least some of these viruses their protein containers are not truly icosahedral, a unique site being created associated with minor structural proteins and one end of the genomic RNA. Clearly disrupting the formation of such unique sites would have seriously deleterious effects on infection. We are proposing to identify vital RNA sequences/motifs within a few test plant viruses that are involved in PS-mediated assembly and early RNA uncoating. These RNA fragments will be co-expressed in plants during viral infection and the consequences for viral titre assayed. Reductions in viral titre will be direct proof of our hypotheses and open novel anti-viral opportunities.
Planned Impact
Pathways to impact: RNA viruses are major threats to human & animal health, as well as to crop yields. For example, Foot and Mouth Disease Virus (FMDV) has recently been the cause of substantial economic damage to UK farming and exports. Novel ways to control such pathogens are therefore urgently required. Our goal here is to demonstrate that the viral genomic RNAs are viable drug targets because of their vital cooperative roles in assembly and disassembly, and that small molecules can be used to inhibit such processes. We will also establish a medium throughput screening assay for such compounds. Obtaining direct support from UK BigPharma is currently difficult because most of them have moved their anti-viral programmes abroad. One benefit of the work proposed will be to demonstrate that the basic innovative science that can improve such applied programmes is actively being developed in the UK. The work proposed is very timely since the Universities of York Helsinki & Leeds have just filed a patent on the potential utility of interfering with the PS-CP interactions that form the core of the new approach. Work carried out under the auspices of this grant during Year 1 will therefore be part of the exemplification of these claims. It is vital to establish that the PS-mediated assembly mechanism is functional in vivo and the best way to achieve this is in plants. This has an immediate potential practical value, and one of us (GL, BBSRC Innovator of the Year, 2012) is perfectly placed to publicise our work to industry.
Advance in knowledge base: Our recent discoveries highlight the importance of understanding the roles of viral RNA genomes in assembly and disassembly. The PS-mediated mechanism and the realisation that "icosahedral" virus capsids are not completely symmetrical are at the cutting edge of basic structural virology. They potential transform our ability to interfere with conserved and vital aspects of these viral lifecycles and have obvious potential application.
Benefit to other disciplines: The outcomes of the experiments planned here will be of widespread benefit for virologists working on the molecular mechanism of viral infection and assembly in the field of ssRNA viruses.
Dissemination of results: Our work will be published in appropriate international journals and presented at the international meetings for which travel funds are sought. Targeted discussions with industry will also be held at appropriate points during the grant period, i.e. especially during Year 3 when the results from plant infections will become known.
Social and economic impact: Many important scientific advances are only found to be useful many years after the original discovery. The work here proposes to test the inferences from novel insights into fundamental biological processes. It is both required to confirm that such mechanisms are operating in vivo and to demonstrate that there could be direct benefits in the medium term for improved novel anti-viral strategies.
Advance in knowledge base: Our recent discoveries highlight the importance of understanding the roles of viral RNA genomes in assembly and disassembly. The PS-mediated mechanism and the realisation that "icosahedral" virus capsids are not completely symmetrical are at the cutting edge of basic structural virology. They potential transform our ability to interfere with conserved and vital aspects of these viral lifecycles and have obvious potential application.
Benefit to other disciplines: The outcomes of the experiments planned here will be of widespread benefit for virologists working on the molecular mechanism of viral infection and assembly in the field of ssRNA viruses.
Dissemination of results: Our work will be published in appropriate international journals and presented at the international meetings for which travel funds are sought. Targeted discussions with industry will also be held at appropriate points during the grant period, i.e. especially during Year 3 when the results from plant infections will become known.
Social and economic impact: Many important scientific advances are only found to be useful many years after the original discovery. The work here proposes to test the inferences from novel insights into fundamental biological processes. It is both required to confirm that such mechanisms are operating in vivo and to demonstrate that there could be direct benefits in the medium term for improved novel anti-viral strategies.
Organisations
People |
ORCID iD |
Reidun Twarock (Principal Investigator) |
Publications
Bingham R
(2021)
Encyclopedia of Virology
Patel N
(2015)
Revealing the density of encoded functions in a viral RNA.
in Proceedings of the National Academy of Sciences of the United States of America
Patel N
(2017)
Rewriting nature's assembly manual for a ssRNA virus.
in Proceedings of the National Academy of Sciences of the United States of America
Rolfsson Ó
(2016)
Direct Evidence for Packaging Signal-Mediated Assembly of Bacteriophage MS2.
in Journal of molecular biology
Stockley PG
(2016)
Bacteriophage MS2 genomic RNA encodes an assembly instruction manual for its capsid.
in Bacteriophage
Twarock R
(2019)
RNA-Mediated Virus Assembly: Mechanisms and Consequences for Viral Evolution and Therapy.
in Annual review of biophysics
Description | We have discovered multiple dispersed packaging signals, that can be targeted by novel antiviral drugs. |
Exploitation Route | The packaging signals are potential drug targets, and insights from the work can also be used in the design of gene vectors. |
Sectors | Agriculture, Food and Drink,Healthcare,Pharmaceuticals and Medical Biotechnology |
Description | The packaging signal we discovered together with collaborators are novel anti-viral drug targets, and can also be used in gene vector design. |
First Year Of Impact | 2015 |
Sector | Agriculture, Food and Drink,Healthcare,Pharmaceuticals and Medical Biotechnology |
Impact Types | Societal,Economic |
Description | Understanding RNA Packaging Signals In Foot-and-mouth Disease Virus (FMDV) For Improved Vaccine Production |
Amount | £421,800 (GBP) |
Funding ID | BB/V008323/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 11/2020 |
End | 10/2023 |
Description | Wellcome Trust Investigator Award |
Amount | £2,400,000 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2016 |
End | 03/2021 |
Title | VIRAL PACKAGING SIGNALS |
Description | We disclose packaging signals of RNA viruses, in particular viruses of the family Picornaviridae or Retroviridae, pharmaceutical compositions comprising anti-viral agents and screening methods enabling the identification of anti-viral agents based on the amino acid binding co-ordinates of capsid proteins to which said packaging signals interact. |
IP Reference | WO2018078369 |
Protection | Patent application published |
Year Protection Granted | 2018 |
Licensed | No |
Impact | Seeking industrial investment. |
Title | VIRUS LIKE PARTICLE |
Description | The disclosure relates to the assembly of Virus Like Particles [VLPs] using packaging native and artificial packaging signals and their use in vaccines and immunological compositions and the methods of vaccination or immunisation against human and animal viral pathogens. |
IP Reference | WO2018220371 |
Protection | Patent application published |
Year Protection Granted | 2018 |
Licensed | No |
Impact | Seeking industrial investment. |
Description | 'Discovery of packaging signal mediated assembly' covered by radio outlets including BBC Radio 5, Radio Berkshire, BBC Radio York, Telegraph |
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 | Press coverage of the work I'm doing 'Discovery of packaging signal mediated assembly' |
Year(s) Of Engagement Activity | 2015 |
Description | 'YorkTalk2016' talk (University of York) on 'Mathematics and the fight against viral infections' |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | A talk showing how the power of mathematical modeling came to the aid of biologists attempting to understand how viruses are constructed. The work opens up the possibility of novel strategies for antiviral therapy. This cutting edge research is revealing new insights into seemingly intractable problems and shows what can be achieved when different disciplines pool their talents. |
Year(s) Of Engagement Activity | 2016 |
URL | https://www.york.ac.uk/research/yorktalks/2016/ |
Description | 2015 London Mathematical Society Gresham College Lecture 'Geometry: A New Weapon in the Fight Against Viruses' at the Museum of London |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | An overview of the latest advances in mathematical virology, and how more and more scientists are turning to group theory, graph theory and dynamical systems to model how viruses form and evolve in multiple clinical contexts - ultimately to improve patient outcomes. "It is fascinating for me to see how mathematics can help address open problems in virology and significantly contribute to the development of new anti-viral strategies against important viral threats, and it has been a pleasure to share this excitement with the audience." |
Year(s) Of Engagement Activity | 2015 |
URL | https://www.lms.ac.uk/editorial/2015-lmsgresham-college-lecture |
Description | Colloquium talk (University of Bristol): 'A Paradigm Shift in Our Understanding of Virus Assembly Opens up New Avenues for Antiviral Intervention' |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | A general colloquium talk about my research. |
Year(s) Of Engagement Activity | 2017 |
Description | Colloquium talk (University of Hamburg, Germany) 'Viruses and Geometry: New Mechanistic Insights into Virus Assemby and Evolution' |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | A talk about my research. |
Year(s) Of Engagement Activity | 2016 |
Description | Colloquium talk (University of Warwick): ' Viruses and geometry - new insights into virus structure and the mechanisms underpinning infection A talk for a wider academic audience'' |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | A colloquium talk. |
Year(s) Of Engagement Activity | 2014 |
Description | Edinburgh International Science Festival 2015: Geometry: A Secret Weapon in the Fight Against Viruses |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Outreach |
Year(s) Of Engagement Activity | 2015 |
URL | http://www.sciencefestival.co.uk/mediaLibrary/other/english/6285.pdf |
Description | Invited colloquium talk in the 'Virtual Virology Lecture Series' at University College London 'The mechanism and evolutionary consequences of packaging signal mediated assembly (and further extensions to Hepatitis B virus and HIV)' |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Virtual Virology Lecture Series aimed at a general academic audience speaking about 'The mechanism and evolutionary consequences of packaging signal mediated assembly (and further extensions to Hepatitis B virus and HIV)'. |
Year(s) Of Engagement Activity | 2016 |
Description | Invited conference talk (University of Cambridge) 'Follow the yellow brick road: New insights into Virus structure, Assembly and Evolution' |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | A talk about my research. |
Year(s) Of Engagement Activity | 2016 |
Description | Invited conference talk: Packaging signal mediated assembly Identification of a Nucleation Complex Groningen 2016 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Biophysics: Mini-colloquium on Physics of Protein Nanoshells at the European Physical Society: Condensed Matter Division meeting (Groningen, 2016, invited talk). |
Year(s) Of Engagement Activity | 2016 |
Description | Invited talk |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | invited talk at the International Conference on Virus Assembly organised by Prof Polly Roy in madeira |
Year(s) Of Engagement Activity | 2018 |
Description | Invited talk (at Pirbright, UK) 'More than a passive passenger: Viral RNAs play vital cooperative roles in virus assembly' |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Talk for the Pirbright Seminar Series at The Pirbright Institute, formerly known as the Institute for Animal Health, a world leading centre of excellence in research and surveillance of virus diseases of farm animals and viruses that spread from animals to humans; working to enhance capability to contain, control and eliminate these economically and medically important diseases, the Institute's highly innovative fundamental and applied bioscience contributes to global food security and health, improving quality of life for animals and people. |
Year(s) Of Engagement Activity | 2014 |
Description | Invited talk at Physical Virology Gordon Research Conference - 'A Code Hidden Within a Code: Deciphering RNA-Encoded Assembly Instructions in Viral Genomes for Applications in Bionanotechnology and Anti-Viral Therapy'. Ventura, California, USA, January 2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Talk title: A Code Hidden Within a Code: Deciphering RNA-Encoded Assembly Instructions in Viral Genomes for Applications in Bionanotechnology and Anti-Viral Therapy |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.grc.org/physical-virology-conference/2019/ |
Description | Invited talk at the Annual Meeting of the American Society of Virology, Madison, Wisconsin, USA, June 2017 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Invited talk |
Year(s) Of Engagement Activity | 2017 |
URL | https://www.emedevents.com/c/medical-conferences-2017/american-society-for-virology-asv-36rd-annual-... |
Description | Plenary conference talk at Boston University July 2016 (SIAM BIO): 'Follow the Yellow Brick Road: New Insights into Virus structure, Assembly and Evolution' |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | SIAM conference on Mathematics in the Life Sciences plenary talk. |
Year(s) Of Engagement Activity | 2016 |
Description | Plenary lecture at the Spring Conference in Bioinformatics - 'Solving a Viral Enigma: Discovery of a hidden code in RNA viral genomes provides a new perspective on viral evolution and anti-viral therapy'. Oregon State University, April 2017 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Lecture title: Solving a Viral Enigma: Discovery of a hidden code in RNA viral genomes provides a new perspective on viral evolution and anti-viral therapy |
Year(s) Of Engagement Activity | 2017 |
URL | https://cgrb.oregonstate.edu/spring-conference/previous-spring-conferences/2017-spring-conference |
Description | Press coverage for discovery of packaging signals in parechoviruses Nature Comms. 8 (5) 2017 |
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 | The research was also featured on various outlets including: Fox News, Cleveland: http://fox8.com/2017/02/23/crucial-step-forward-in-the-search-to-cure-the-common-cold/ CNN: http://edition.cnn.com/2017/02/23/health/how-to-cure-common-cold/ BBC Radio York, Sheffield, Humberside and Lincolnshire. Daily Mail: http://bit.ly/2kTToGO. |
Year(s) Of Engagement Activity | 2017 |
Description | Public talk (University of Edinburgh) 'Geometry: A secret weapon in the fight against viruses' |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | A public talk explaining my research. |
Year(s) Of Engagement Activity | 2016 |
Description | York Festival of Ideas (University of York 2015): Viruses: Mathematical visualisations joint talk with artist Briony Thomas |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Following a collaboration between designer Briony Thomas of the University of Leeds and mathematical virologist Reidun Twarock of the University of York, this interactive exhibition explores recent advances in our understanding of viruses. |
Year(s) Of Engagement Activity | 2015 |
URL | http://yorkfestivalofideas.com/2015/exhibitions/viruses/ |
Description | mbi Emphasis Workshop talk (The Ohio State University) 'Assembly of ssRNA viruses II: Consequences of Packaging Signal Mediated Assembly for Viral Evolution' |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Abstract: Packaging signals provide an instruction manual for efficient virus assembly and thus place constraints on the evolution of single-stranded RNA genomes. This talk will cover the consequences of packaging signal-mediated assembly for viral evolution. It will discuss the geometry of the implicitly define fitness landscapes underpinning the evolutionary dynamics and the consequences of viral geometry for evolution. |
Year(s) Of Engagement Activity | 2015 |
URL | https://mbi.osu.edu/event/?id=823#abstracts |