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Professor John Doorbar

Professor John Doorbar

Professor of Viral Pathogenesis

Division of Virology

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

Office Phone: +44 (0)1223 333734

Research themes

Virology:

Division

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. Egawa N, Wang Q, Griffin HM, Murakami I, Jackson D, Mahmood R, Doorbar J. (2017) HPV16 and 18 genome amplification show different E4-dependence, with 16E4 enhancing E1 nuclear accumulation and replicative efficiency via its cell cycle arrest and kinase activation functions.  PLoS Pathog. 2017 Mar 17;13(3):e1006282.  PMID:28306742

  2. Egawa N, Doorbar J. (2017) The low-risk papillomaviruses.  Virus Res. 231 p119-127  PMID: 28040475

  3. Meuris F, Carthagena L, Jaracz-Ros A, Gaudin F, Cutolo P, Deback C, Xue Y, Thierry F, Doorbar J, Bachelerie F. (2016) The CXCL12/CXCR4 Signaling Pathway: A New Susceptibility Factor in Human Papillomavirus Pathogenesis. PLoS Pathog. Dec 5;12(12) PMID: 27918748

  4. Schiffman M, Doorbar J, Wentzensen N, de Sanjosé S, Fakhry C, Monk BJ, Stanley MA, Franceschi S. (2016) Carcinogenic human papillomavirus infection.  Nat Rev Dis Primers. Dec 1;2:16086.  PMID: 27905473

  5. Ganti K, Massimi P, Manzo-Merino J, Tomaić V, Pim D, Playford MP, Lizano M, Roberts S, Kranjec C, Doorbar J, Banks L. (2016) Interaction of the Human Papillomavirus E6 Oncoprotein with Sorting Nexin 27 Modulates Endocytic Cargo Transport Pathways.PLoS Pathog. 20;12(9)  PMID:27649450

  6. Kranjec C, Doorbar J. (2016)  Human papillomavirus infection and induction of neoplasia: a matter of fitness.  Curr Opin Virol. 2016 Oct;20:129-136.  PMID:2760090

  7. Ajiro M, Tang S, Doorbar J, Zheng ZM.(2016) Serine/Arginine-Rich Splicing Factor 3 and Heterogeneous Nuclear Ribonucleoprotein A1 Regulate Alternative RNA Splicing and Gene Expression of Human Papillomavirus 18 through Two Functionally Distinguishable cis Elements. J Virol. 29;90(20): 9138-52. PMID:27489271

  8. Doorbar, J. (2016) Pathogenesis of Papillomaviruses in Humans. In ‘Human Emerging and Re-Imerging Infections. Viral and Parasitic Infections. Volume 1’ Edited by Sunit Kumar Singh. Published by John Wiley & Sons, New Jersey, USA. ISBN: 978-1-118-64471-3
  9. Griffin H, and Doorbar J (2016) Detection of Papillomavirus Gene Expression Patterns in Tissue Sections.  Current Protocols 6;41:14B.7.1-14B.7.20.  PMID:27153382

  10. Doorbar, J. (2016) Model Systems of HPV-Associated Disease. J.Pathol 238(2):166-79. PMID: 26456009

  11. van Baars R, Griffin H, Wu Z, Soneji YJ, van de Sandt MM, Arora R, van der Marel J, Ter Harmsel B, Jach R, Okon K, Huras H, Jenkins D, Quint WG, Doorbar J. (2015) Investigating Diagnostic Problems of CIN1 and CIN2 Associated With High-risk HPV by Combining the Novel Molecular Biomarker PanHPVE4 With P16INK4a.  Am J Surg Pathol. 2015 Sep 16. [Epub ahead of print]  http://pmid.us/23816390

  12. Luttmer R, Dijkstra MG, Snijders PJ, Jordanova ES, King AJ, Pronk DT, Foresta C, Garolla A, Hompes PG, Berkhof J, Bleeker MC, Doorbar J, Heideman DA, Meijer CJ. (2015) Presence of human papillomavirus in semen of healthy men is firmly associated with HPV infections of the penile epithelium. Fertility & Sterility 2015 Oct;104(4):838-844.e8. doi: 10.1016/j.fertnstert.2015.06.028. [Epub 2015 Jul 23.]
    http://www.ncbi.nlm.nih.gov/pubmed/26211884  

  13. Doorbar J, Egawa N, Griffin H, Kranjec C, Murakami I (2015) Human papillomavirus molecular biology and disease
    association.
    Rev Med Virol. 2015 Mar;25 Suppl 1:2-23. doi: 10.1002/rmv.1822.
    Review. PMID: 25752814  

  14. Griffin H, Soneji Y, Van Baars R, Arora R, Jenkins D, van de Sandt M, Wu Z, Quint W,
    Jach R, Okon K, Huras H, Singer A, Doorbar J. (2015) Stratification
    of HPV-induced cervical pathology using the virally encoded molecular marker E4
    in combination with p16 or MCM.
    Mod Pathol. 2015 Jul;28(7):977-93. doi:10.1038/modpathol.2015.52. Epub 2015
    May 8.PMID: 25953390  

  15. Egawa N, Egawa K, Griffin H, Doorbar J. (2015) Human Papillomaviruses; Epithelial Tropisms, and the Development of Neoplasia. Viruses 2015 Jul 16;7(7):3863-90. doi: 10.3390/v7072802. PMID: 26193301

  16. Quint KD, Genders RE, de Koning MN, Borgogna C, Gariglio M, Bouwes Bavinck JN,
    Feltkamp MC. and Doorbar J. (2015) Human
    Beta-papillomavirus infection and keratinocyte carcinomas.
    J Pathol. 2015 Jan;235(2):342-54. doi: 10.1002/path.4425.
    PMID: 25131163

  17. Landini MM, Borgogna C, Peretti A, Doorbar J, Griffin H, Mignone F, Lai A, Urbinati L, Matteelli A,
    Gariglio M, De Andrea M. (2015) Identification of the skin virome in a boy with
    widespread human papillomavirus-2-positive warts that completely regressed
    after administration of tetravalent human papillomavirus vaccine.
    Br J Dermatol. 2015 Aug;173(2):597-600. doi:
    10.1111/bjd.13707. Epub 2015 Jun 25. PMID: 25639663

  18. Borgogna C, Lanfredini S, Peretti A, De Andrea M, Zavattaro E, Colombo E, Quaglia M, Boldorini R, Miglio U, Doorbar J, Bavinck JN, Quint KD, de Koning MN, Landolfo S, Gariglio M. (2014) Improved detection reveals active β-papillomavirus infection in skin lesions from kidney transplant recipients. Mod Pathol. 2014 Aug;27(8):1101-15. doi: 10.1038/modpathol.2013.240. Epub 2014 Jan 3. Erratum in: Mod Pathol. 2014 Jun;27(6):917.PMID: 24390217

  19. Landini MM, Borgogna C, Peretti A, Colombo E, Zavattaro E, Boldorini R, Miglio U, Doorbar J, Ravanini P, Kumar R, Moratto D, Badolato R, De Andrea M, Gariglio M. (2014) α- and β-papillomavirus infection in a young patient with an unclassified primary T-cell immunodeficiency and multiple mucosal and cutaneous lesions.
    J Am Acad Dermatol. 2014 Jul;71(1):108-15.e1. doi: 10.1016/j.jaad.2014.01.859. Epub 2014 Mar 4. PMID: 24612648

  20. Borgogna C, Landini MM, Lanfredini S, Doorbar J, Bouwes Bavinck JN, Quint KD, de Koning MN, Genders RE,
    Gariglio M. (2014) Characterization
    of skin lesions induced by skin-tropic α- and β-papillomaviruses in a patient
    with epidermodysplasia verruciformis.
    Br J Dermatol.
    2014 Dec;171(6):1550-4. doi: 10.1111/bjd.13156. Epub 2014 Nov 30.  PMID: 24902472

  21. Maglennon, G., McIntosh, P.B. and Doorbar, J. (2014) Immunosuppression Facilitates the Reactivation of Latent
    Papillomavirus Infection at sites of Previous Disease J.Virol. 88, p710 – 716

  22. Bosch FX, Broker TR, Forman D, Moscicki AB, Gillison ML, Doorbar J, Stern PL, Stanley M, Arbyn M, Poljak M, Cuzick J, Castle PE, Schiller JT, Markowitz LE, Fisher WA, Canfell K, Denny LA, Franco EL, Steben M, Kane MA, Schiffman M, Meijer CJ, Sankaranarayanan R, Castellsagué X, Kim JJ, Brotons M, Alemany L, Albero G, Diaz M, de Sanjosé S (2013) Comprehensive control of human papillomavirus infections and related diseases. Vaccine. 2013 Dec 31;31

    Suppl 5:F1-31. doi: 10.1016/j.vaccine.2013.10.001.        PMID: 24331745
    Suppl 6:G1-31. doi: 10.1016/j.vaccine.2013.10.002.       PMID: 24331817
    Suppl 7:H1-31. doi: 10.1016/j.vaccine.2013.10.003.       PMID: 24332295
    Suppl 8:I1-31. doi: 10.1016/j.vaccine.2013.07.026.        PMID: 24229716

  23. Hufbauer, M., Biddle, A., Borgogna, C., Gariglio, M., Doorbar, J., Storey, A., Pfister, H., Mackenzie, I and Akgül, B. (2013) Expression of Betapapillomavirus Oncogenes increase the number of Keratinocytes with Stem Cell-like properties.  J.Virol 87: p12158-12165 http://www.ncbi.nlm.nih.gov/pubmed/24006432

  24. Doorbar, J. (2013) The E4 Protein; Structure, Function and Patterns of Expression. Virology 445: p80-98 http://authors.elsevier.com/sd/article/S0042682213004108<span style="text-decoration: underline; "></span>

  25. Doorbar, J. (2013) Latent Papillomavirus Infections and their Regulation. Current Opinions in Virology 4: p416-421 http://pmid.us/23816390

  26. Doorbar, J. (2013) Cervical Cancer (Section III: Molecular Pathology) in Molecular Oncology: Causes of Cancer and Targets for Treatment” Editors: Edward Gelmann, Charles Sawyers, and Frank Rauscher III. Cambridge University Press, Cambridge, UK, published 31, 12, 2013, ISBN 0521876621

  27. Cid      Arregui, A., Gariglio, P., Kanda, T. and Doorbar, J. (2012) High-Risk Human Papillomaviruses: Towards a better Understanding of the Mechanisms      of Viral Transformation, Latency and Immune-Escape. Open Virology Journal 6:160-162  http://pmid.us/23346264

  28. Maglennon,G.A. and Doorbar,J. (2012) The Biology of Papillomavirus Latency.  Open Virology Journal 6:190-197 http://pmid.us/23341854

  29. Griffin,H., Wu,Z., Marnane,R., Dewar,V., Molijn,A., Quint,W., Struyf,F., Colau,B., Jenkins,
    D., and Doorbar, J. (2012) E4 Antibodies Facilitate Detection and Type-Assignment of Active HPV Infection in Cervical Disease.   PLOS
    One.
    12:e49974 http://pmid.us/22911498  

  30. Sahab,Z., Sudarshan,S.R., Liu,X., Zhang,Y., Kirilyuk,A.,Kamonjoh,C.M., Simic,V., Dai, Y.,
    Byers,S.W., Doorbar,J.,
    Suprynowicz,F.A., and Schlegel,R. (2012)
    Quantitative Measurement of HPV-16 E5 Oncoprotein Levels in Epithelial Cell
    Lines by Mass Spectrometry. J.Virol
    86:9465-9473 http://pmid.us/22740411   

  31. Doorbar,J., Quint,W., Banks,L., Bravo,I., Stoler,M.,
    Broker,T. and Stanley,M.A. (2012)
    The Biology and Life-Cycle Of Human Papillomaviruses. (ICO/IARC Monograph
    Chapter).  Vaccine 30(S5):55-70 http://pmid.us/22911498  

  32. Sperling,T., Ołdak,M., Walch,B., Wickenhauser,C., Doorbar,J.,
    Pfister,H., Malejczyk,M., Majewski,S., Keates,A.C. and Smola,S. (2012) Human Papillomavirus Type
    8 Interferes with a Novel C/EBP Beta-Mediated Mechanism of Keratinocyte CCL20
    Chemokine Expression and Langerhans Cell Migration.  PLOS
    Pathogens. 8 (7):e1002833  http://pmid.us/22911498  
     
  33.  Isaacson,E.R., Wang,Q., Pagliarulo,E., Roberts,I., Untersperger,C., Coleman,N., Griffin,H. and Doorbar,J.  (2012)
    HPV oncogene expression correlates with CIN-like phenotype in a model of early cervical disease. J.Virol. 86:6358-6364 http://pmid.us/22457518 

  34. Tan,C-L, Gunaratne,J., Lai,D., Carthagena,L.,      Wang,Q., Xue,Y.Z., Quek,L.S, Doorbar,J.,      Bachelerie,F., Thierry,F. and S.Bellanger (2012) HPV-18 E2^E4 chimera: 2 new spliced transcripts and      proteins induced by keratinocyte differentiation. Virology 429(1):47-56. http://pmid.us/22541938

  35. Doorbar, J. (2012) HPV infection, the nature of theinfected cell, and the outcome of cervical disease. HPV Today 25 p4-5
    (www.hpvtoday.com)

  36. Borgogna,C., Zavattaro,E.,      De Andrea,M., Griffin,H., Dell’Oste,V., Azzimonti,B., Landini,M.M., Peh,W., Pfister,H., Doorbar,J.,      Landolfo,S., andGariglio,M. (2012)      Characterisation of Beta Papillomavirus E4 Expression in Tumours from      Epidermodysplasia Verruciformis Patients and in Experimental Models. Virology 423(2):195-204. http://pmid.us/22217391

  37. Quint,W., Jenkins,D., Molijn,A., Struijk,L.,      Sandt,M.v.d., Doorbar,J., Mols,J., v Hoof,C., Hardt,K.,      Struyf,F. and Colau,B. (2012) One      Virus One Lesion—Individual Components of CIN Lesions Contain a Specific      HPV Type. J      Pathol. 227(1):62-71.      http://pmid.us/22127961