Geometry as a key to the virosphere: Unmasking the fundamental roles of geometry in virus structure, evolution and pathology

Lead Research Organisation: University of York
Department Name: Mathematics

Abstract

Society faces major challenges from viral diseases. The recent Zika and Ebola outbreaks are only two examples of the devastating impact of viral illnesses on human health, and viral pathogens infecting agriculturally important livestock and plants simultaneously reduce food production and inflict great annual financial losses worldwide. Viruses, however, also have positive impacts on health and ecology. They balance and stabilise our gut microbiome, preventing serious illnesses such as certain autoimmune diseases, and influence our climate owing to their roles in carbon cycling in the oceans. It is therefore paramount to better understand virus structure and function across the entire virosphere in order to control, and even take advantage of, viruses in medicine and biotechnology.
I have demonstrated previously that mathematical approaches developed in tandem with experimentalists are drivers of discovery of functionally crucial structural viral features, revealing their novel functional roles in viral life cycles, and enabling their exploitation in therapy and biotechnology. Previously developed mathematical approaches were geared towards a specific major sub-group of the virosphere. In this research programme, I will both broaden and deepen the development of novel mathematical techniques. Working in close collaboration with leading experimental groups, at a larger scale, I will identify functionally important geometric viral features in a number of major groups of viruses. This will include: geometric strand assortment in multipartite viruses, such as the major agricultural pathogen Bluetongue virus; the assembly of retroviruses like HIV, with applications to the construction of virus-like particles from viral components as vectors for gene editing and therapy; and the structure and evolution of viruses important for the gut microbiome and marine ecology. By linking structural features with their functions, I will address open problems regarding drivers of evolution in one of the simplest yet most important groups of biological entities. This approach will unmask evolutionarily conserved functional features that can be used as novel targets in anti-viral therapy, for the development of novel safer vaccines or repurposed in bionanotechnology.

Planned Impact

Society faces major challenges from viral disease, and novel anti-viral targets and strategies are therefore urgently required. I have demonstrated previously that mathematical techniques and models, when developed in close collaboration with experiment, can act as drivers of discovery of such solutions. Indeed, together with experimental collaborators, I am a named inventor on three patents that exploit our discovery of an RNA-encoded virus assembly instruction manual in single-stranded RNA viruses.
In this research programme, I will tackle geometric challenges in viruses that are not amenable to the approaches developed previously, but that are expected to also have functionally important contacts between viral genome and capsid protein that could act as novel drug targets. Examples include the common cold virus and poliovirus. After cleavage of the major capsid protein, these viruses undergo structural transitions of their capsids concomitant with rearrangements of their genomes, as an essential step in becoming infectious. I will develop novel geometric approaches to characterise such contacts between viral genome and capsid in these viruses at a molecular scale, and develop models that enable us to study their functions. Please refer to the Statement of Support of my Project Partner Peter Stockley. I expect that further patents will arise from this work, with the potential of developing anti-viral drugs against viruses such as polio and the common cold virus, as well as a broad range of other viruses that are amenable to the techniques that we are developing in this programme. A further example is Bluetongue virus, an agriculturally important virus of ruminants for which my Project Partner Polly Roy is an internationally leading expert. The mathematical techniques that I am developing for this collaboration will potentially also apply to other multipartite viruses such as influenza and measles.
The mechanistic understanding of how structural features contribute to efficient formation of viral particles will moreover be used to design virus-like particles (VLPs) by repurposing viral components. This will enable the production of safe vaccines (noninfectious repurposed capsid shells, presenting neutralising viral epitopes to the immune system on the outer surfaces), which is of strong interest to the WHO Polio Eradication Initiative, and will contribute to the demand for ever more effective vaccines against larger numbers of pathogens.
VLPs derived from lentiviruses such as HIV, which are another focus of this research programme in collaboration with my Project Partner Greg Towers, have major potential applications in gene therapy, for example in the treatment of cancer. Insights from this research programme such as the cooperative role of the genome in assembly will make a significant contribution to the design of lentiviral VLPs by making their assembly more efficient, which is currently a bottleneck in the widespread therapeutic exploitation of these gene vectors.
Finally, my geometric understanding of phages and their roles in the gut will contribute to a better understanding of how the equilibrium between phages and bacteria can be rebalanced as a means to prevent severe illnesses such as some autoimmune diseases, and ultimately may also help understand the role of marine phages in carbon cycling, a process that is important for our climate.

Publications

10 25 50
 
Description In collaboration with Antoni Luque I have discovered a design principle for icosahedral structures that has solved several open problems in structural virology. It contains the seminal Caspar-Klug Theory as a special case. A paper reporting these results has been submitted to Nature Communications.

In collaboration with my PDRA Giuliana Indelicato I have developed a mathematical model of the structural capsid transitions in the common cold virus, that is an essential step in its life cycle and a prerequisite for infectivity of the virus.

I have developed a mathematical model of infectious interfering particles exploiting packaging signal mediated assembly.
Exploitation Route These results support the development of novel anti-viral strategies.
Sectors Agriculture, Food and Drink,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description Results regarding the new design principle for icosahedral architectures are being rendered in a VR environment for outreach purposes. They also support the development of novel forms of anti-viral intervention.
First Year Of Impact 2018
Sector Education,Healthcare,Manufacturing, including Industrial Biotechology,Culture, Heritage, Museums and Collections,Pharmaceuticals and Medical Biotechnology
Impact Types Cultural,Societal,Economic

 
Description BBC Documentary with Hannah Fry 
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 Contribution to a BBC Documentary with Hannah Fry: "Magic Numbers: Hannah Fry's Mysterious World of Maths", Episode 1 ("Numbers as God")
Shown 11th October 2018 at 3pm on BBC4 (https://www.bbc.co.uk/programmes/b0bn6wtp)
Year(s) Of Engagement Activity 2018
URL https://ihavenotv.com/numbers-as-god-magic-numbers-hannah-frys-mysterious-world-of-maths
 
Description Invited talk at the IMA Early Career Mathematicians' Autumn Conference, UCL, November 2018 - 'Viruses and Geometry: Mathematics enables discovery in virology and creates new opportunities in bionanotechnology and anti-viral therapy' 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Talk title: Viruses and Geometry: Mathematics enables discovery in virology and creates new opportunities in bionanotechnology and anti-viral therapy
Year(s) Of Engagement Activity 2018
URL https://ima.org.uk/10273/ima-early-career-mathematicians-autumn-conference-2018/
 
Description Plenary talk at Mathematics Professional Festival - for high school teachers, Department of Mathematical Sciences, University of Copenhagen, November 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Talk title: Viruses under the mathematical microscope: An opportunity to demonstrate the impact of mathematics in biology in the classroom environment
Year(s) Of Engagement Activity 2018
 
Description Seminar talk at the University of Nottingham, March 2019 - 'Viruses and Geometry: New Insights into Virus Structure, Assembly, Evolution and Therapy' 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Talk title: Viruses and Geometry: New Insights into Virus Structure, Assembly, Evolution and Therapy
Year(s) Of Engagement Activity 2019
URL https://www.nottingham.ac.uk/mathematics/events/cmmb/seminarcmmb12032019.aspx
 
Description Talk at Maths Week Ireland, National Concert Hall Dublin, October 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Talk about my work and its applications in health to an audience of 16 year old transition year students (interlude between Junior Certificate and Leaving Certificate courses).
Year(s) Of Engagement Activity 2018
URL http://www.mathsweek.ie/2018/
 
Description Talk at The Roslin Institute, Edinburgh, November 2018 - 'An RNA-encoded virus assembly manual: mechanisms and consequences for viral evolution and therapy' 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Talk title: An RNA-encoded virus assembly manual: mechanisms and consequences for viral evolution and therapy
Year(s) Of Engagement Activity 2018