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

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.

Publications

10 25 50

 
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