The cellular and molecular mechanisms of foot-and-mouth disease virus and bluetongue virus infection
Lead Research Organisation:
THE PIRBRIGHT INSTITUTE
Department Name: UNLISTED
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
The aim of this project is to advance understanding of the mechanisms of infection by foot-and-mouth disease virus (FMDV) and bluetongue virus (BTV) especially to determine how these pathogens subvert host functions to effect their replication. The principal areas of our work (including the IAH Research Fellow Dr. Toby Tuthill) are the mechanisms of FMDV and BTV endocytosis, host-cell membrane penetration, and FMDV replication and assembly. Understanding the early steps in viral entry has relevance to pathogenesis as these events often determine target cell selection within the host, which dictates the site of infection and the host’s response. Through these studies we hope to gain a better understanding of how these viruses replicate and inform applied research for control of these important animal pathogens.
We use an integrated approach combining biochemical, molecular and cell biology techniques with reverse genetics, microscopy (confocal and electron microscopy) and structural biology to ask fundamental questions about how virus particles attach to cells, how they are internalized by endocytosis, how they use host-cell membranes for replication and how new viruses are assembled. We are using our knowledge of FMDV receptors to improve growth of vaccine strains of the virus in cultured cells and to develop integrin receptors as 'universal' virus-capture ligands for use in diagnostic assays. To achieve replication, FMDV dramatically reorganizes internal cellular membranes to provide specialized sites for formation of viral replication complexes. My laboratory also studies these events as we wish to determine what triggers membrane rearrangements in infected cells, as well as the cellular origin of the replication membranes and what properties make them favourable for replication. We also contribute the Global FMDV Research Alliance (GFRA) that works towards achieving better disease control by the production of novel vaccines and antiviral reagents.
We use an integrated approach combining biochemical, molecular and cell biology techniques with reverse genetics, microscopy (confocal and electron microscopy) and structural biology to ask fundamental questions about how virus particles attach to cells, how they are internalized by endocytosis, how they use host-cell membranes for replication and how new viruses are assembled. We are using our knowledge of FMDV receptors to improve growth of vaccine strains of the virus in cultured cells and to develop integrin receptors as 'universal' virus-capture ligands for use in diagnostic assays. To achieve replication, FMDV dramatically reorganizes internal cellular membranes to provide specialized sites for formation of viral replication complexes. My laboratory also studies these events as we wish to determine what triggers membrane rearrangements in infected cells, as well as the cellular origin of the replication membranes and what properties make them favourable for replication. We also contribute the Global FMDV Research Alliance (GFRA) that works towards achieving better disease control by the production of novel vaccines and antiviral reagents.
Planned Impact
unavailable
Publications
Berryman S
(2013)
Positively charged residues at the five-fold symmetry axis of cell culture-adapted foot-and-mouth disease virus permit novel receptor interactions.
in Journal of virology
Berryman S
(2016)
Foot-and-mouth disease virus replicates independently of phosphatidylinositol 4-phosphate and type III phosphatidylinositol 4-kinases.
in The Journal of general virology
Chamberlain K
(2015)
Identification of a novel cell culture adaptation site on the capsid of foot-and-mouth disease virus.
in The Journal of general virology
Howson E
(2018)
Direct detection and characterization of foot-and-mouth disease virus in East Africa using a field-ready real-time PCR platform
in Transboundary and Emerging Diseases
Howson ELA
(2018)
Direct detection and characterization of foot-and-mouth disease virus in East Africa using a field-ready real-time PCR platform.
in Transboundary and emerging diseases
Kotecha A
(2015)
Structure-based energetics of protein interfaces guides foot-and-mouth disease virus vaccine design.
in Nature structural & molecular biology
Panjwani A
(2014)
Capsid protein VP4 of human rhinovirus induces membrane permeability by the formation of a size-selective multimeric pore.
in PLoS pathogens
Porta C
(2013)
Rational engineering of recombinant picornavirus capsids to produce safe, protective vaccine antigen.
in PLoS pathogens
Porta C
(2013)
Efficient production of foot-and-mouth disease virus empty capsids in insect cells following down regulation of 3C protease activity.
in Journal of virological methods
Seago J
(2013)
An infectious recombinant foot-and-mouth disease virus expressing a fluorescent marker protein.
in The Journal of general virology
| Description | Established replicon technology for foot-and-mouth disease virus (FMDV), which will allow detailed experiments to investigate the mechanisms of FMDV replication. Identified the role of a picornavirus, viral protein (VP4) in inducing membrane permeability, which strongly suggests a mechanism for transfer of the viral RNA genome into cells. Established technology for producing FMDV empty capsid for use as vaccines Produced a recombinant FMDV expressing a fluorescent marker which will be useful for studies of FMDV pathogenesis Kotecha A, Seago J, Scott K, Burman A, Loureiro S, Ren J, Porta C.. Stuart DI. (2015). Structure-based energetics of protein interfaces guides foot-and-mouth disease virus vaccine design. Nature structural & molecular biology, 22 (10), pp. 788-94 Chamberlain K, Fowler VL, Barnett PV, Gold S, Wadsworth J, Knowles NJ, Jackson T. (2015). Identification of a novel cell culture adaptation site on the capsid of foot-and-mouth disease virus. The Journal of general virology, 96 (9), pp. 2684-92 Berryman S, Lohmann V, Jackson T, Harak C, Moffat K. (2016). Foot-and-mouth disease virus replicates independently of phosphatidylinositol 4-phosphate and type III phosphatidylinositol-4-kinases. Journal of General Virology, Shimmon G, Wood B, Morris A, Mioulet V, Grazioli S, Brocchi E, Berryman S.. Jackson T. (2016). Truncated Bovine Integrin Alpha-v/Beta-6 as a Universal Capture Ligand for FMD Diagnosis. PLOS ONE, 11 (8), pp. e0160696 |
| Exploitation Route | Our discoveries will enable; Detailed studies of for foot-and-mouth disease virus (FMDV) replication. The development of antivirals that inhibit picornavirus replication. The production of safer FMDV vaccines. Recombinant FMDV expressing a fluorescent marker which will be useful for studies of FMDV pathogenesis |
| Sectors | Agriculture Food and Drink Pharmaceuticals and Medical Biotechnology Other |
| Description | Our discoveries will enable; Detailed studies of for foot-and-mouth disease virus (FMDV) replication. The development of antivirals that inhibit picornavirus replication. The production of safer FMDV vaccines. Recombinant FMDV expressing a fluorescent marker which will be useful for studies of FMDV pathogenesis |
| Sector | Other |
| 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 |