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Dr John Doorbar

Director of Research

Department of Pathology
University of Cambridge
Tennis Court Road
Cambridge
CB2 1QP

Office Phone: +44 (0)1223 333734

Research themes

Virology:

Research Interests

Human papilloma viruses (HPVs) are estimated to cause around 5% of all human cancers [1] as well as serious benign disease in some individuals. There are no antivirals against HPV and treatment options for precursor lesions, end-stage cancers and papillomas typically involve surgical removal, destructive agents, or in some instances local immune modulation. Disease recurrence is a significant problem. Although vaccination represents a partial solution in some settings, it has only marginal value for those already infected. In such cases, a better understanding of the disease process and how this results from HPV infection is a crucial requirement.

Research in the HPV laboratory seeks to understand how HPV infection leads to disease. Over the past few years we have built up a coherent picture of the papillomavirus life cycle in differentiating epithelium (reviewed in [2,3]; [4,5,6,7]). We have also developed a repertoire of unique antibodies [7,8,9], and a variety of techniques to following HPV replication in raft cultures in vitro [4,5,6,10,11,12,13], in animal models [14,15,16] and in patient tissue samples [8,17,18,19] that will allow the detailed analysis of HPV growth, the host systems with which they interact and the clinical conditions that ensue.

Our future work will focus specifically on:

  1. the molecular basis of PV life-cycle de-regulation that occurs at particular epithelial sites (i.e. epithelial tropisms), and how this can lead to neoplasia of different grades.
  2. the mechanisms of lesion-formation and lesion regression, and in particular, the role of the wound-healing response in infection.
  3. the events that lead to, and which regulate papillomavirus latency, asymptomatic infection and reactivation.

Insights from this work will continue to be used to develop better diagnostic approaches for cervical (and other) HPV disease, and to develop effective methods for of interfering with HPV replication and persistence following infection.

 
Doorbar Research
Our past work has identified important changes in viral gene expression that underlie the development of HPV-associated cervical intraepithelial neoplasias (top left). A series of molecular studies that we have published in the Journal of Virology over the last few years has revealed how one of the viral proteins (E4) is post-transcriptionally modified to facilitate its deposition as amyloid-like fibrils (bottom left). An image of E4 staining in a patient biopsy of a cervical neoplasia prepared using a cross-reactive E4 antibody prepared in the lab is shown in the MRC Strategic Plan www.mrc.ac.uk/strategicplan to illustrate to potential of such research in the development of diagnostic strategies for disease stratification.
  • Group members:
    Dr Nagayasu Egawa
    Dr Heather Griffin
    Dr Christian Kranjec
    Dr Isao Murakami
    Karen Wolfrey

    Professor Margaret Stanley FMedSci Hon FRCOG
  • Collaborators/Affiliated members

    Dr Jane Sterling PhD FRCP
    Hon. Consultant Dermatologist
    Addenbrookes Hospital
    Cambridge
    jcs12@cam.ac.uk

    Dr Robin Crawford MD
    Consultant Gynaecological Oncologist
    Addenbrookes Hospital
    Cambridge
    robin.crawford@addenbrookes.nhs.uk

Key Publications

  1. de Martel C et al. (2012) Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncology 13: 607-615.
  2. Doorbar J et al. (2012) The Biology and Life Cycle of Human Papillomaviruses. Vaccine 30 (S5) p55-70.
  3. Doorbar J (2006) Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci (Lond) 110: 525-541.
  4. Khan J et al. (2011) Role of calpain in the formation of human papillomavirus type 16 E1^E4 amyloid fibers and reorganization of the keratin network. Journal of Virology 85: 9984-9997.
  5. McIntosh PB et al. (2008) Structural analysis reveals an amyloid form of the human papillomavirus type 16 E1^E4 protein and provides a molecular basis for its accumulation. J Virol 82: 8196-8203.
  6. Wang Q et al. (2009) Phosphorylation of the human papillomavirus type 16 E1^E4 protein at T57 by ERK triggers a structural change that enhances keratin binding and protein stability. J Virol 83: 3668-3683.
  7. Wang Q et al. (2004) Functional analysis of the human papillomavirus type 16 E1^E4 protein provides a mechanism for in vivo and in vitro keratin filament reorganization. J Virol 78: 821-833.
  8. Griffin H et al. (2012) E4 Antibodies Facilitate Detection and Type-Assignment of Active HPV Infection in Cervical Disease. PLOS One 12 e49974
  9. Colau B et al. (2010) Exploratory Study Report for new technologies and biomarkers on HPV-16/18 associated CIN2+cases at final analysis of Study 580299/008 (HPV-008) (Development Phase III).
  10. McIntosh PB et al. (2010) E1^E4-mediated keratin phosphorylation and ubiquitylation: a mechanism for keratin depletion in HPV16-infected epithelium. Journal of Cell Science 123: 2810-2822.
  11. Davy C et al. (2009) A novel interaction between the human papillomavirus type 16 E2 and E1--E4 proteins leads to stabilization of E2. Virology 394: 266-275.
  12. Davy CE et al. (2005) Human Papillomavirus Type 16 E1^E4-Induced G2 Arrest Is Associated with Cytoplasmic Retention of Active Cdk1/Cyclin B1 Complexes. J Virol 79: 3998-4011.
  13. Isaacson Wechsler E et al. (2012) Reconstruction of human papillomavirus type 16-mediated early-stage neoplasia implicates e6/e7 deregulation and the loss of contact inhibition in neoplastic progression. Journal of Virology 86: 6358-6364.
  14. Maglennon GA et al. (2011) Persistence of viral DNA in the epithelial basal layer suggests a model for papillomavirus latency following immune regression. Virology 414: 153-163.
  15. Peh WL et al. (2004) The viral E4 protein is required for the completion of the cottontail rabbit papillomavirus productive cycle in vivo. J Virol 78: 2142-2151.
  16. Peh WL et al. (2002) Life cycle heterogeneity in animal models of human papillomavirus-associated disease. J Virol 76: 10401-10416.
  17. Middleton K et al. (2003) Organization of human papillomavirus productive cycle during neoplastic progression provides a basis for selection of diagnostic markers. J Virol 77: 10186-10201.
  18. Quint W et al. (2012) One virus, one lesion--individual components of CIN lesions contain a specific HPV type. The Journal of Pathology 227: 62-71.
  19. Borgogna C et al. (2012) Characterization of beta papillomavirus E4 expression in tumours from Epidermodysplasia Verruciformis patients and in experimental models. Virology 423: 195-204.