Professor David J. Blackbourn

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Research Interests

Infectious agents, including viruses, are associated with up to 20% of human cancers. The Blackbourn laboratory studies two such viruses: Kaposi's sarcoma-associated herpesvirus (KSHV) and Merkel cell polyomavirus (MCV or MCPyV).

Our major interest is in how viruses cause disease and modulate the immune response. KSHV provides a model for most of our studies, but the impact of our work could extend to other viruses or host/pathogen interactions. Our main research topics in this context are: (i) how KSHV interacts with the DNA damage response.  (ii) How KSHV modulates the type I interferon (alpha & beta) response. (iii) How KSHV deregulates antigen-specifc T cell responses. (iii) What are the consequences of KSHV infection on endothelial cell biology, including cell-cell interactions and regulating leukocyte recruitment.



For MCV, our interests lie in understanding the tumour microenvironment and how it contributes to the pathogenesis of Merkel cell carcinoma.

Research Collaborations

Prof Blackbourn collaborates with colleagues throughout the world, including:

Dr Roger Grand, University of Birmingham

Dr Andrew Hislop, University of Birmingham

Professor Christian Munz, University of Zurich

Dr Mohamed Mutocheluh, Kwame Nkrumah University of Science and Technology (KNUST), Ghana

Dr Neil Steven, University of Birmingham

Professor Rolf Renne, University of Florida

Blackbourn Laboratory Methods

http://www.surrey.ac.uk/biomed/blackbournlabmethods/ 

Contact Me

E-mail:
Phone: 01483 68 6499

Find me on campus
Room: 15 AX 01


My office hours

Please contact Stephanie Perriam for an appointment.

Publications

Journal articles

  • Stakaitytė G, Nwogu N, Dobson S, Knight L, Wasson C, Salguero Bodes F, Blackbourn D, Blair G, Mankouri J, Macdonald A, Whitehouse A. (2017) 'Merkel cell polyomavirus small T antigen drives cell motility via Rho-GTPase-induced filopodia formation'. American Society for Microbiology Journal of Virology, 92 (2) Article number e00940-17 , pp. 1-21.

    Abstract

    Cell motility and migration is a complex, multi-step, and multi-component process, intrinsic to progression and metastasis. Motility is dependent on the activity of integrin receptors and Rho-family GTPases resulting in the remodelling of the actin cytoskeleton and formation of various motile actin-based protrusions. Merkel cell carcinoma (MCC) is an aggressive skin cancer with a high likelihood of recurrence and metastasis. Merkel cell polyomavirus (MCPyV) is associated with the majority of MCC cases, and MCPyV-induced tumourigenesis largely depends on the expression of the small tumour antigen (ST). Since the discovery of MCPyV, a number of mechanisms have been suggested to account for replication and tumourigenesis, but to date, little is known about potential links between MCPyV T antigen expression and the metastatic nature of MCC. Previously, we have described the action of MCPyV ST on the microtubule network and how this impacts on cell motility and migration. Here we demonstrate that MCPyV ST affects the actin cytoskeleton, to promote the formation of filopodia, through a mechanism involving the catalytic subunit of protein phosphatase 4 (PP4C). We also show that MCPyV ST-induced cell motility is dependent upon the activity of Rho-family GTPases Cdc42 and RhoA. In addition, our results indicate that the MCPyV ST-PP4C interaction results in the dephosphorylation of β1 integrin, likely driving the cell motility pathway. These findings describe a novel mechanism by which a tumour virus induces cell motility, which may ultimately lead to cancer metastasis and provides opportunities and strategies for targeted interventions for disseminated MCC.

  • McHugh D, Caduff N, Barros M, Rämer P, Raykova A, Murer A, Landtwing V, Quast I, Styles C, Spohn M, Fowotade A, Delecluse H, Papoudou-Bai A, Lee Y, Kim J, Middeldorp J, Schulz T, Cesarman E, Zbinden A, Capaul R, White R, Allday M, Niedobitek G, Blackbourn D, Grundhoff A, Münz C. (2017) 'Persistent KSHV Infection Increases EBV-Associated Tumor Formation In Vivo via Enhanced EBV Lytic Gene Expression'. Elsevier Cell Host & Microbe, 22 (1), pp. 61-73.e7.

    Abstract

    The human tumor viruses Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) establish persistent infections in B cells. KSHV is linked to primary effusion lymphoma (PEL), and 90% of PELs also contain EBV. Studies on persistent KSHV infection in vivo and the role of EBV co-infection in PEL development have been hampered by the absence of small animal models. We developed mice reconstituted with human immune system components as a model for KSHV infection and find that EBV/KSHV dual infection enhanced KSHV persistence and tumorigenesis. Dual-infected cells displayed a plasma cell-like gene expression pattern similar to PELs. KSHV persisted in EBV-transformed B cells and was associated with lytic EBV gene expression, resulting in increased tumor formation. Evidence of elevated lytic EBV replication was also found in EBV/KSHV dually infected lymphoproliferative disorders in humans. Our data suggest that KSHV augments EBV-associated tumorigenesis via stimulation of lytic EBV replication.

  • Narkwa P, Blackbourn D, Mutocheluh M. (2017) 'Aflatoxin B1 inhibits the type 1 interferon response pathway via STAT1 suggesting another mechanism of hepatocellular carcinoma'. BioMed Central Infectious Agents and Cancer, 12 (17)

    Abstract

    Background Aflatoxin B1 (AFB1) contamination of food is very high in most sub-Saharan African countries. AFB1 is known to cause hepatocellular carcinoma (HCC) by inducing mutation in the tumour suppressor gene TP53. The number of new HCC cases is high in West Africa with an accompanying high mortality. The type I interferon (IFN) pathway of the innate immune system limits viral infections and exerts its anti-cancer property by up-regulating tumour suppressor activities and pro-apoptotic pathways. Indeed, IFN-α is reported to show significant protective effects against hepatic fibrogenesis and carcinogenesis. However, the mechanism behind AFB1 deregulation of the type I interferon (IFN) signalling pathway, with consequent HCC is largely unknown. This current study seeks to test the hypothesis that AFB1 inhibits the type I IFN response by directly interfering with key signalling proteins and thus increase the risk of HCC in humans.

    Methods We evaluated the effects of AFB1 on the type I IFN signalling pathway using IFN stimulated response element (ISRE)-based luciferase reporter gene assay. In addition, the effects of AFB1 on the transcript levels of JAK1, STAT1 and OAS3 were assessed by real-time quantitative polymerase chain reaction (RT-qPCR) and confirmed by immunoblot assay.

    Results Our results indicated that AFB1 inhibited the type I IFN signalling pathway in human hepatoma cell line HepG2 cells by suppressing the transcript levels of JAK1, STAT1 and OAS3. AFB1 also decreased the accumulation of STAT1 protein.

    Conclusion The inhibition of the type I IFN anti-cancer response pathway by AFB1 suggest a novel mechanism by which AFB1 may induce hepatocellular carcinoma in humans.

  • Hollingworth R, Skalka GL, Stewart GS, Hislop AD, Blackbourn DJ, Grand RJ. (2015) 'Activation of DNA Damage Response Pathways during Lytic Replication of KSHV.'. Viruses, Switzerland: 7 (6), pp. 2908-2927.
  • Amini AA, Solovyova AS, Sadeghian H, Blackbourn DJ, Rezaee SA. (2014) 'Structural properties of a viral orthologue of cellular CD200 protein: KSHV vOX2.'. Virology, United States: 474, pp. 94-104.
  • Knight LM, Stakaityte G, Wood JJ, Abdul-Sada H, Griffiths DA, Howell GJ, Wheat R, Blair GE, Steven NM, Macdonald A, Blackbourn DJ, Whitehouse A. (2014) 'Merkel cell polyomavirus small T antigen mediates microtubule destabilization to promote cell motility and migration.'. J Virol, United States: 89 (1), pp. 35-47.
  • Othman Z, Sulaiman MK, Willcocks MM, Ulryck N, Blackbourn DJ, Sargueil B, Roberts LO, Locker N. (2014) 'Functional analysis of Kaposi's sarcoma-associated herpesvirus vFLIP expression reveals a new mode of IRES-mediated translation.'. RNA, United States: 20 (11), pp. 1803-1814.

    Abstract

    Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus, the etiological agent of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). One of the key viral proteins that contributes to tumorigenesis is vFLIP, a viral homolog of the FLICE inhibitory protein. This KSHV protein interacts with the NFκB pathway to trigger the expression of antiapoptotic and proinflammatory genes and ultimately leads to tumor formation. The expression of vFLIP is regulated at the translational level by an internal ribosomal entry site (IRES) element. However, the precise mechanism by which ribosomes are recruited internally and the exact location of the IRES has remained elusive. Here we show that a 252-nt fragment directly upstream of vFLIP, within a coding region, directs translation. We have established its RNA structure and demonstrate that IRES activity requires the presence of eIF4A and an intact eIF4G. Furthermore, and unusually for an IRES, eIF4E is part of the complex assembled onto the vFLIP IRES to direct translation. These molecular interactions define a new paradigm for IRES-mediated translation.

  • Wheat R, Roberts C, Waterboer T, Steele J, Marsden J, Steven NM, Blackbourn DJ. (2014) 'Inflammatory cell distribution in primary Merkel cell carcinoma'. Cancers, 6 (2), pp. 1047-1064.
  • Jeffery HC, Wheat RL, Blackbourn DJ, Nash GB, Butler LM. (2013) 'Infection and transmission dynamics of rKSHV.219 in primary endothelial cells.'. J Virol Methods, Netherlands: 193 (1), pp. 251-259.
  • McKimmie CS, Singh MD, Hewit K, Lopez-Franco O, Le Brocq M, Rose-John S, Lee KM, Baker AH, Wheat R, Blackbourn DJ, Nibbs RJB, Graham GJ. (2013) 'An analysis of the function and expression of D6 on lymphatic endothelial cells'. AMER SOC HEMATOLOGY BLOOD, 121 (18), pp. 3768-3777.
  • Jacobs SR, Gregory SM, West JA, Wollish AC, Bennett CL, Blackbourn DJ, Heise MT, Damania B. (2013) 'The Viral Interferon Regulatory Factors of Kaposi's Sarcoma-Associated Herpesvirus Differ in Their Inhibition of Interferon Activation Mediated by Toll-Like Receptor 3'. AMER SOC MICROBIOLOGY JOURNAL OF VIROLOGY, 87 (2), pp. 798-806.
  • Butler LM, Jeffery HC, Wheat RL, Long HM, Rae PC, Nash GB, Blackbourn DJ. (2012) 'Kaposi's sarcoma-associated herpesvirus inhibits expression and function of endothelial cell major histocompatibility complex class II via suppressor of cytokine signaling 3.'. J Virol, United States: 86 (13), pp. 7158-7166.
  • Damania B, Blackbourn DJ. (2012) 'Innate barriers to viral infection'. Future Microbiology, 7 (7), pp. 815-822.
  • Misstear K, Chanas SA, Rezaee SA, Colman R, Quinn LL, Long HM, Goodyear O, Lord JM, Hislop AD, Blackbourn DJ. (2012) 'Suppression of antigen-specific T cell responses by the Kaposi's sarcoma-associated herpesvirus viral OX2 protein and its cellular orthologue, CD200.'. J Virol, United States: 86 (11), pp. 6246-6257.
  • Berhane S, Aresté C, Ablack JN, Ryan GB, Blackbourn DJ, Mymryk JS, Turnell AS, Steele JC, Grand RJ. (2011) 'Adenovirus E1A interacts directly with, and regulates the level of expression of, the immunoproteasome component MECL1.'. Virology, United States: 421 (2), pp. 149-158.
  • Mutocheluh M, Hindle L, Aresté C, Chanas SA, Butler LM, Lowry K, Shah K, Evans DJ, Blackbourn DJ. (2011) 'Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor-2 inhibits type 1 interferon signalling by targeting interferon-stimulated gene factor-3.'. J Gen Virol, England: 92 (Pt 10), pp. 2394-2398.
  • Butler LM, Jeffery HC, Wheat RL, Rae PC, Townsend K, Alkharsah KR, Schulz TF, Nash GB, Blackbourn DJ. (2011) 'Kaposi's sarcoma-associated herpesvirus infection of endothelial cells inhibits neutrophil recruitment through an interleukin-6-dependent mechanism: a new paradigm for viral immune evasion.'. J Virol, United States: 85 (14), pp. 7321-7332.
  • Jackson BR, Boyne JR, Noerenberg M, Taylor A, Hautbergue GM, Walsh MJ, Wheat R, Blackbourn DJ, Wilson SA, Whitehouse A. (2011) 'An Interaction between KSHV ORF57 and UIF Provides mRNA-Adaptor Redundancy in Herpesvirus Intronless mRNA Export'. PUBLIC LIBRARY SCIENCE PLOS PATHOGENS, 7 (7) Article number ARTN e1002138
  • Taylor GS, Blackbourn DJ. (2011) 'Infectious agents in human cancers: lessons in immunity and immunomodulation from gammaherpesviruses EBV and KSHV.'. Cancer Lett, Ireland: 305 (2), pp. 263-278.
  • Durrington HJ, Upton PD, Hoer S, Boname J, Dunmore BJ, Yang J, Crilley TK, Butler LM, Blackbourn DJ, Nash GB, Lehner PJ, Morrell NW. (2010) 'Identification of a Lysosomal Pathway Regulating Degradation of the Bone Morphogenetic Protein Receptor Type II'. AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC JOURNAL OF BIOLOGICAL CHEMISTRY, 285 (48), pp. 37641-37649.
  • Aresté C, Mutocheluh M, Blackbourn DJ. (2009) 'Identification of caspase-mediated decay of interferon regulatory factor-3, exploited by a Kaposi sarcoma-associated herpesvirus immunoregulatory protein.'. J Biol Chem, United States: 284 (35), pp. 23272-23285.
  • Wang L, Pietrek M, Brinkmann MM, Haevemeier A, Fischer I, Hillenbrand B, Dittrich-Breiholz O, Kracht M, Chanas S, Blackbourn DJ, Schulz TF. (2009) 'Identification and functional characterization of a spliced rhesus rhadinovirus gene with homology to the K15 gene of Kaposi's sarcoma-associated herpesvirus'. SOC GENERAL MICROBIOLOGY JOURNAL OF GENERAL VIROLOGY, 90, pp. 1190-1201.
  • Aresté C, Blackbourn DJ. (2009) 'Modulation of the immune system by Kaposi's sarcoma-associated herpesvirus.'. Trends Microbiol, England: 17 (3), pp. 119-129.
  • Okroj M, Mark L, Stokowska A, Wong SW, Rose N, Blackbourn DJ, Villoutreix BO, Spiller OB, Blom AM. (2009) 'Characterization of the Complement Inhibitory Function of Rhesus Rhadinovirus Complement Control Protein (RCP)'. AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC JOURNAL OF BIOLOGICAL CHEMISTRY, 284 (1), pp. 505-514.
  • Colman R, Blackbourn DJ. (2008) 'Risk factors in the development of Kaposi's sarcoma.'. AIDS, England: 22 (13), pp. 1629-1632.
  • Mark L, Proctor DG, Blackbourn DJ, Blom AM, Spiller OB. (2008) 'Separation of decay-accelerating and cofactor functional activities of Kaposi's sarcoma-associated herpesvirus complement control protein using monoclonal antibodies'. BLACKWELL PUBLISHING IMMUNOLOGY, 123 (2), pp. 228-238.
  • Ye F-C, Blackbourn DJ, Mengel M, Xie J-P, Qian L-W, Greene W, Yeh I-T, Graham D, Gao S-J. (2007) 'Kaposi's sarcoma-associated herpesvirus promotes angiogenesis by inducing angiopoietin-2 expression via AP-1 and Ets1'. AMER SOC MICROBIOLOGY JOURNAL OF VIROLOGY, 81 (8), pp. 3980-3991.
  • Mark L, Spiller OB, Okroj M, Chanas S, Aitken JA, Wong SW, Damania B, Blom AM, Blackbourn DJ. (2007) 'Molecular characterization of the rhesus rhadinovirus (RRV) ORF4 gene and the RRV complement control protein it encodes'. AMER SOC MICROBIOLOGY JOURNAL OF VIROLOGY, 81 (8), pp. 4166-4176.
  • Rezaee SA, Cunningham C, Davison AJ, Blackbourn DJ. (2006) 'Kaposi's sarcoma-associated herpesvirus immune modulation: an overview.'. J Gen Virol, England: 87 (Pt 7), pp. 1781-1804.
  • Aresté C, Blackbourn DJ. (2006) 'HIV Tat-mediated transcriptional regulation of proteasome protein cleavage specificity.'. Biochem J, England: 396 (2), pp. e13-e15.
  • Spiller OB, Mark L, Blue CE, Proctor DG, Aitken JA, Blom AM, Blackbourn DJ. (2006) 'Dissecting the regions of virion-associated Kaposi's sarcoma-associated herpesvirus complement control protein required for complement regulation and cell binding'. AMER SOC MICROBIOLOGY JOURNAL OF VIROLOGY, 80 (8), pp. 4068-4078.
  • Fuld S, Cunningham C, Klucher K, Davison AJ, Blackbourn DJ. (2006) 'Inhibition of interferon signaling by the Kaposi's sarcoma-associated herpesvirus full-length viral interferon regulatory factor 2 protein'. AMER SOC MICROBIOLOGY JOURNAL OF VIROLOGY, 80 (6), pp. 3092-3097.

Conference papers

  • Butler LM, Wheat RL, Jeffery HC, Nash GB, Blackbourn DJ. (2009) 'Infection of endothelial cells with Kaposi's sarcoma-associated herpesvirus selectively inhibits recruitment of flowing neutrophils in an inflammatory model'. ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD CYTOKINE, Lisbon, PORTUGAL: Tri-Society Annual Conference of the International-Cytokine-Society/International-Society-of-Interferon-and-Cytokine-Research/Society-of-Leukocyte-Biology 48 (1-2), pp. 51-51.
  • Okroj M, Mark L, Stokowska A, Wong S, Rose N, Blackbourn D, Villoutreix B, Spiller B, Blom A. (2008) 'Characterization of the complement inhibitory function of Rhesus rhadinovirus'. PERGAMON-ELSEVIER SCIENCE LTD MOLECULAR IMMUNOLOGY, Basel, SWITZERLAND: 22nd International Complement Workshop 45 (16), pp. 4172-4173.
  • Mark L, Spiller OB, Blackbourn DJ, Blom AM. (2007) 'Molecular details of the complement regulatory and cell attaching functions of KCP'. PERGAMON-ELSEVIER SCIENCE LTD MOLECULAR IMMUNOLOGY, Beijing, PEOPLES R CHINA: 21st International Complement Workshop 44 (1-3), pp. 213-213.

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