Regulation of cyclin D1 in coronavirus infected cells

Lead Research Organisation: University of Leeds
Department Name: Inst of Molecular & Cellular Biology

Abstract

Viruses are one of the major causes of disease and can lead to significant economic loses in agriculture. Infectious bronchitis virus (IBV), the focus of this grant is no exception and the virus is reported to kill some 15,000,000 poultry annually with associated economic impact. Previous research suggests that many viruses can exploit the cells they infect to help in the growth and production of new viruses. As a result of previous BBSRC funding we have found that IBV also hijacks the host cell to fine tune its infectious cycle. One of the ways it does this is to manipulate what is called the cell cycle by interfering with the very molecules that control this vital cellular pathway. The cell cycle is a mechanism by which normal cells control their growth and production of new cells. The focus of this research proposal is to investigate how IBV interferes with the cell cycle by identify the virus protein(s) responsible and determining the precise mechanism involved. By doing this we aim to develop an in depth understanding of this process that will have broad application to similar viruses and exploit these findings in the development of new vaccines to aid in the control of IBV.

Technical Summary

Many viruses are now believed to alter host cell processes to facilitate virus replication and progeny virus production. One of the major targets is the cell cycle. We were the first group to show that the coronavirus infectious bronchitis virus (IBV), a disease of economic importance (kills approximately 15,000,000 broilers per year), targeted the cell cycle to enhance viral protein synthesis and progeny virus production. Our data indicated that the principal cellular target for virus infection was cyclin D1 which was almost completely ablated in virus infected cells. This proposal has a number of objectives. It seeks to addresses how and why cyclin D1 is ablated, to identify and characterise the virus protein responsible and to exploit this knowledge in the generation of recombinant viruses that are deficient in interacting with the cell cycle and thus are excellent candidates for growth attenuated recombinant live virus vaccines.
 
Description The avian infectious bronchitis virus (IBV) coronavirus is one of the major threats to the poultry industry in the UK and worldwide. New strains are constantly emerging and the need for new vaccines and therapeutic strategies is constant. In order to better understand the pathogenesis of IBV we investigated the interaction of the virus with the host cell, focusing on a process known as the cell cycle and how this affects virus biology. The cell cycle is a series of steps and events that governs the growth and division of cells. As part of this project we characterised how and why IBV interacts with the cell cycle and subverts host cell function to increase the production of new virus particles and control cellular anti-viral signalling.
Exploitation Route This research could be used by industry in a generic manner for boosting the production of virus vaccines in cell culture. Many viruses, including IBV, exploit and alter the cell cycle in order to boost virus productivity and the ak]mount of output infectious virus. As many virus vaccines are now being (or planned) to be produced in cell culture the ability to manipulate the cell cycle exogenously ready for virus infection would lead to an increase in productivity of the virus. There are two exploitation routes one is designing strategies to prevent IBV interacting with the cell cycle to promote virus biology. The other is to exploit this benefit for virus growth for increasing the production of virus in cell culture.
Sectors Manufacturing/ including Industrial Biotechology
 
Description Leverhulme Personal Research Fellowship
Amount £44,015 (GBP)
Organisation The Leverhulme Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2009 
End 05/2011
 
Description Elucidating the interaction of human respiratory syncytial virus with the host cell and sequencing of genetic changes 
Organisation Public Health England
Country United Kingdom 
Sector Public 
PI Contribution Human respiratory syncytial virus (HRSV) is a major paediatric infection and influenza A virus (IAV) like infectious bronchitis virus (IBV) alter the host cell to benefit virus biology. Given our publications from this grant, the Health Protection Agency has funded research in our laboratory to investigate how HRSV interacts with the cell cycle and host cell and for similar work on IAV.
Collaborator Contribution The work on developing the technologies to implement the analysis of ADAR modifications to the HRSV genome allowed us to apply these during the West African Ebola outbreak to study the genome evolution of Ebola. The partners and ourselves applied for joint funding in this area from the EU and also the Food and Drug Administration USA.
Impact Two publications in the journal Nature: Real-time, portable genome sequencing for Ebola surveillance. Quick J, Loman NJ, Duraffour S, Simpson JT, Severi E, Cowley L, Bore JA, Koundouno R, Dudas G, Mikhail A, Ouédraogo N, Afrough B, Bah A, Baum JH, Becker-Ziaja B, Boettcher JP, Cabeza-Cabrerizo M, Camino-Sánchez Á, Carter LL, Doerrbecker J, Enkirch T, García-Dorival I, Hetzelt N, Hinzmann J, Holm T, Kafetzopoulou LE, Koropogui M, Kosgey A, Kuisma E, Logue CH, Mazzarelli A, Meisel S, Mertens M, Michel J, Ngabo D, Nitzsche K, Pallasch E, Patrono LV, Portmann J, Repits JG, Rickett NY, Sachse A, Singethan K, Vitoriano I, Yemanaberhan RL, Zekeng EG, Racine T, Bello A, Sall AA, Faye O, Faye O, Magassouba N, Williams CV, Amburgey V, Winona L, Davis E, Gerlach J, Washington F, Monteil V, Jourdain M, Bererd M, Camara A, Somlare H, Camara A, Gerard M, Bado G, Baillet B, Delaune D, Nebie KY, Diarra A, Savane Y, Pallawo RB, Gutierrez GJ, Milhano N, Roger I, Williams CJ, Yattara F, Lewandowski K, Taylor J, Rachwal P, Turner DJ, Pollakis G, Hiscox JA, Matthews DA, O'Shea MK, Johnston AM, Wilson D, Hutley E, Smit E, Di Caro A, Wölfel R, Stoecker K, Fleischmann E, Gabriel M, Weller SA, Koivogui L, Diallo B, Keïta S, Rambaut A, Formenty P, Günther S, Carroll MW. Nature. 2016 Feb 11;530(7589):228-32. doi: 10.1038/nature16996. Temporal and spatial analysis of the 2014-2015 Ebola virus outbreak in West Africa. Carroll MW, Matthews DA, Hiscox JA, Elmore MJ, Pollakis G, Rambaut A, Hewson R, García-Dorival I, Bore JA, Koundouno R, Abdellati S, Afrough B, Aiyepada J, Akhilomen P, Asogun D, Atkinson B, Badusche M, Bah A, Bate S, Baumann J, Becker D, Becker-Ziaja B, Bocquin A, Borremans B, Bosworth A, Boettcher JP, Cannas A, Carletti F, Castilletti C, Clark S, Colavita F, Diederich S, Donatus A, Duraffour S, Ehichioya D, Ellerbrok H, Fernandez-Garcia MD, Fizet A, Fleischmann E, Gryseels S, Hermelink A, Hinzmann J, Hopf-Guevara U, Ighodalo Y, Jameson L, Kelterbaum A, Kis Z, Kloth S, Kohl C, Korva M, Kraus A, Kuisma E, Kurth A, Liedigk B, Logue CH, Lüdtke A, Maes P, McCowen J, Mély S, Mertens M, Meschi S, Meyer B, Michel J, Molkenthin P, Muñoz-Fontela C, Muth D, Newman EN, Ngabo D, Oestereich L, Okosun J, Olokor T, Omiunu R, Omomoh E, Pallasch E, Pályi B, Portmann J, Pottage T, Pratt C, Priesnitz S, Quartu S, Rappe J, Repits J, Richter M, Rudolf M, Sachse A, Schmidt KM, Schudt G, Strecker T, Thom R, Thomas S, Tobin E, Tolley H, Trautner J, Vermoesen T, Vitoriano I, Wagner M, Wolff S, Yue C, Capobianchi MR, Kretschmer B, Hall Y, Kenny JG, Rickett NY, Dudas G, Coltart CE, Kerber R, Steer D, Wright C, Senyah F, Keita S, Drury P, Diallo B, de Clerck H, Van Herp M, Sprecher A, Traore A, Diakite M, Konde MK, Koivogui L, Magassouba N, Avšic-Županc T, Nitsche A, Strasser M, Ippolito G, Becker S, Stoecker K, Gabriel M, Raoul H, Di Caro A, Wölfel R, Formenty P, Günther S. Nature. 2015 Aug 6;524(7563):97-101.
Start Year 2012