Professor David Dockrell MD FRCPI FRCP(Glas) FACP

Honorary Professor of Infection MedicineProfessor David Dockrell

MRC/UoE Centre for Inflammation Research
The University of Edinburgh
Room C2.30
The Queen's Medical Research Institute
47 Little France Crescent
Edinburgh
EH16 4TJ

Tel: 0131 242 6581
Fax: 0131 242 6578
Email: David.Dockrell@ed.ac.uk

Biography:

I am a clinician scientist. My undergraduate degree was from Trinity College Dublin and I then trained in Dublin before undertaking specialty training in Infectious Diseases at the Mayo Clinic, USA. During this period I developed my interests in macrophage immunology and in the regulation of apoptosis.

I joined the University of Sheffield in 1998 and developed my research with a particular focus on how macrophage apoptosis regulates innate immune responses with particular emphasis on pneumococcal infection. In 2005 I received a Wellcome Senior Clinical fellowship.

I moved from Sheffield in 2016 to become Professor of infection Medicine at the University of Edinburgh with an interest in HIV medicine and infections in immunocompromised hosts.

Research Interests:

My research interests stem from understanding how macrophages contribute to the innate immune response against bacteria and viruses. We have developed a variety of tissue culture models as well as several in vivo models using the pneumococcus as a probe. We have applied these to a variety of other infections including Staphylococcus aureus, Neisseria meningitidis and Pseudomonas aeruginosa as well as HIV-1 and Influenza A virus infection. In particular we are investigating how the host response can utilize induction of apoptosis to enhance microbial killing and regulation of the inflammatory response and how this can be manipulated by specific pathogens.

My current work focuses on understanding how microbial killing in organelles such as the phagolysosome sensitizes the macrophage to initiate a programme of apoptosis which involves downregualtion of the anti-apoptotic Bcl-2 family member Mcl-1 and ultimately leads to a mitochondrial pathway of apoptosis. We investigate how macrophage phenotype or specific pathogens can alter this host response.

I am also interested in how clinical diseases may alter susceptibility by modulating macrophage host responses. As part of the MRC-ABPI COPD consortium we are investigating how COPD modifies macrophage responses to respiratory bacteria. Our group also are examining how HIV-1 modifies macrophage responses to pneumococci in the lung.

My work interdigitates closely with that of Professor Moira Whyte (University of Edinburgh), investigation of myeloid cell biology and the regulation of pulmonary inflammation and pulmonary disease with Professor Ian Sabroe (University of Sheffield) and Professor Moira Whyte, and studies on in vivo models of inflammation with Dr Helen Marriott. Our proteomic studies are carried out with Prof Mark Dickman and formerly also with Phillip Wright (Chemical and Process Engineering).

Teaching Interests:

My teaching focuses on the pathogenesis and clinical features of HIV and other infectious diseases.

Professional Activities:

  • 2013 - 17 MRC Clinical Training and Development panel (Clinical Fellowship panel)
  • 2012 - 16 Academic Director Communicable Diseases Sheffield teaching Hospitals
  • 2012 - 16 Chair South Yorkshire and Humber CLRN Microbiology and Infection Local Specialty Group
  • 2012 - 16 External examiner Liverpool School of Tropical Medicine MSc in Infectious Diseases
  • 2011/12 Health Research Board Ireland panel member (2012 Senior clinical fellowship panel)
  • 2011- Meningitis UK advisory panel member
  •  2010- Member of the Commission on Human Medicines - Anti Infectives/AIDS/Hepatology Expert Advisory Group
  • 2016 - 2021 SHIELD (The Universities of SHeffield, Edinburgh, BIrmingham and Newcastle Led Partnership to Develop Host Defence Therapeutics)
    AMR consortium modulating host defence against AMR bacteria
  • “Optimising Innate Host Defence to Combat Antimicrobial Resistance” MRC 3.5M Dec 2016-Dec 2021

Current Projects:

  • Investigation of respiratory viruses in vivo and their impact on the innate response to bacterial infection (with Prof. Ian Sabroe)
  • Mechanisms and consequences of host-mediated macrophage apoptosis in pneumococcal pneumonia.
  • A proteomics approach to examine how bacteria inhibit macrophage apoptosis to subvert innate immune responses.
  • The role of the alveolar macrophage and neutrophils in the pathogenesis of Staphylococcus aureus pneumonia (as part of the Infectious Disease Cross Cutting Network led by Simon Foster)
  • Investigation of mechanisms, impact and therapeutic targeting of microbial colonisation in COPD (with Profs Whyte and Sabroe and MRC-ABPI consortium collaborators)
  • Lead for SHIELD (The Universities of SHeffield, Edinburgh, BIrmingham and Newcastle Led Partnership to Develop Host Defence Therapeutics)
    AMR consortium modulating host defence against AMR bacteria “Optimising Innate Host Defence to Combat Antimicrobial Resistance” MRC £3.5M Dec 2016-Dec 2021
  • C0-I for MRF The Medical Research Foundation National Antimicrobial Resistance PhD Programme (PI Mathew Avison, Bristol) £2.3M 2017-2022

Editorial Positions:

  • 2015 - Frontiers microbiology and then cellular and infection immunology

Publications:

  1. Bewley MA, Budd RC, Ryan E, Cole J, Collin Pi, Marshall J, Kolsum U, Beech G, Emes RD, Tcherniaeva I, Berbers GAM, Walmsley SR, Donaldson G, Wedzichia JA, Kilty J, Rumsey W, Sanchez Y, Brightling CE, Donnelly LE, Barnes PJ, SinghDJ, Whyte MKB, Dockrell DH . Opsonic phagocytosis in chronic obstructive pulmonary disease is enhanced by Nrf2 agonists.  American Journal of Respiratory and Critical Care Medicine 2018 in press doi: 10.1164/rccm.201705 0903OC. PMID:29547002.
  2. Boldock E, Surewaard BGJ, Shamarina D, Na M, Fei Y, Ali A, Williams A, Pollitt EDJ, Szkuta P, Morris P, Prajsnar TK, McCoy KD, Jin T, Dockrell DH, van Strijp JAG, Kubes P, Renshaw SA, Foster SJ. Human skin commensals augment Staphylococcus aureus pathogenesis. Nature Microbiology 2018: 3; 881-90.
  3. Collini PJ, Bewley MA, Mohasin M, Marriott HM, Miller RF, Gerretti AM, Beloukas A, Papadimitropoulos A, Read RC, Noursadeghi M, Dockrell DH. HIV gp120 in lungs of ART-treated individuals impairs alveolar macrophage responses to pneumococci. American Journal of Respiratory and Critical Care Medicine 2018 : 197; 1604-15.
  4. Sadiku P, Wilson JA, Dickinson RS, Murphy F, Harris AJ, Lewis A, Sammut D, Mirchandani AS, Ryan E, Watts ER, Thompson AAR, Marriott HM, Dockrell DH, Taylor, CT, Schneider M, Maxwell PH, Chilvers EH, Mazzone M, Moral V, Pugh CW, Ratcliffe PJ, Schofield CJ, Ghesquiere B, Carmeliet P, Whyte MK, Walmsley SR. Prolyl hydroxylase 2 inactivation enhances glycogen storage and promotes excessive neutrophilic responses. J. Clin. Invest. 2017: 127; 3407-20. doi: 10.1172/JCI90848
  5. Salamaga B, Prajsnar TK, Jareño-Martinez A, Willemse J, Bewley MA, Chau F, Belkacem B, Meijer AH, Dockrell DH, Renshaw SA, Mesnage S. Bacterial size matters: Multiple mechanisms controlling septum cleavage and diplococcus formation are critical for the virulence of the opportunistic pathogen Enterococcus faecalis. PLoS Pathogens. 2017: 13 (7): e1006526. doi: 10.1371/journal.ppat.1006526
  6. Bewley MA, Preston JA, Mohasin M, Marriott HM, Budd RC, Swales J, Collini P, Greaves DR, Craig RW, Brightling CE, Donnelly LE, Barnes PJ, Singh D, Shapiro SD, Whyte MKB, Dockrell DH. Impaired mitochondrial microbicidal responses in chronic obstructive pulmonary disease macrophages. American Journal of Respiratory and Critical Care Medicine 2017: 196; 845-55.
  7. Thompson AAR, Dickinson RS, Murphy F, Thomson JP, Marriott HM, Tavares A, Willson J, Williams L, Lewis A, Mirchandani A, Dos Santos Coelho P, Doherty C, Ryan E, Watts E, Morton NM, Forbes S, Stimson RH, Hameed AG, Arnold N, Preston JP, Lawrie A, Finesguerra V, Mazzone M, Sidikhu P, Goveia J, Taverna F, Carmeliet P, Foster SJ, Chilvers ER, Cowburn AS, Dockrell DH, Johnson RS, Meehan RR, Whyte MKB, Walmsley SA. Hypoxia determines survival outcomes of bacterial infection through HIF-1alpha dependent re-programming of leukocyte metabolism. Science Immunology 2017: 2; 8 pii: eeal2861 doi 10.1126/sciimmunol.aal2861
  8. Jubrail J, Morris P, Bewley MA, Stoneham S, Johnston SA, Foster SJ, Peden AA, Read RC, Marriott HM, Dockrell DH (2015) Inability to sustain intraphagolysosomal killing of Staphylococcus aureus predisposes to bacterial persistence in macrophages. Cellular Microbiology, 18(1), 80-96.
  9. Bewley MA, Naughton M, Preston J, Mitchell A, Holmes A, Marriott HM, Read RC, Mitchell TJ, Whyte MKB, Dockrell DH (2014) Pneumolysin Activates Macrophage Lysosomal Membrane Permeabilization and Executes Apoptosis by Distinct Mechanisms without Membrane Pore Formation. mBio, 5(5).
  10. Thompson AAR, Elks PM, Marriott HM, Eamsamarng S, Higgins KR, Lewis A, Williams L, Parmar S, Shaw G, McGrath EE, Formenti F, Van Eeden FJ, Kinnula VL, Pugh CW, Sabroe I, Dockrell DH, Chilvers ER, Robbins PA, Percy MJ, Simon C, Johnson RS, Renshaw SA, Whyte MK, Walmsley SR (2013) Hypoxia-inducible factor 2α regulates key neutrophil functions in humans, mice and zebrafish. Blood, 123(3), 366-376.
  11. Marriott HM, Daigneault M, Thompson AAR, Walmsley SR, Gill SK, Witcher DR, Wroblewski VJ, Hellewell PG, Whyte MKB, Dockrell DH (2012) A decoy receptor 3 analogue reduces localised defects in phagocyte function in pneumococcal pneumonia. Thorax, 67(11), 985-992.
  12. Daigneault M, De Silva TI, Bewley MA, Preston JA, Marriott HM, Mitchell AM, Mitchell TJ, Read RC, Whyte MKB, Dockrell DH (2012) Monocytes regulate the mechanism of T-cell death by inducing Fas-mediated apoptosis during bacterial infection. PLoS Pathog, 8(7), e1002814.
  13. Bewley MA, Pham TK, Marriott HM, Noirel J, Chu H-P, Ow SY, Ryazanov AG, Read RC, Whyte MKB, Chain B, Wright PC, Dockrell DH (2011) Proteomic evaluation and validation of cathepsin D regulated proteins in macrophages exposed to Streptococcus pneumoniae. Mol Cell Proteomics, 10(6), M111.008193.
  14. Walmsley SR, Chilvers ER, Thompson AA, Vaughan K, Marriott HM, Parker LC, Shaw G, Parmar S, Schneider M, Sabroe I, Dockrell DH, Milo M, Taylor CT, Johnson RS, Pugh CW, Ratcliffe PJ, Maxwell PH, Carmeliet P, Whyte MKB (2011) Prolyl hydroxylase 3 (PHD3) is essential for hypoxic regulation of neutrophilic inflammation in humans and mice. J Clin Invest, 121(3), 1053-1063.
  15. Bewley MA, Marriott HM, Tulone C, Francis SE, Mitchell TJ, Read RC, Chain B, Kroemer G, Whyte MKB & Dockrell DH (2011) A cardinal role for cathepsin d in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci. PLoS Pathog, 7(1), e1001262.#Marriott HM, Jackson LE, Wilkinson TS, Simpson AJ, Mitchell TJ, Buttle DJ, Cross SS, Ince PG, Hellewell PG, Whyte MKB, Dockrell DH (2008) Reactive oxygen species regulate neutrophil recruitment and survival in pneumococcal pneumonia. Am J Respir Crit Care Med, 177(8), 887-895.
  16. Bianchi SM, Prince LR, McPhillips K, Allen L, Marriott HM, Taylor GW, Hellewell PG, Sabroe I, Dockrell DH, Henson PW, Whyte MKB (2008) Impairment of apoptotic cell engulfment by pyocyanin, a toxic metabolite of Pseudomonas aeruginosa. Am J Respir Crit Care Med, 177(1), 35-43.Marriott HM, Bingle CD, Read RC, Braley KE, Kromer G, Hellewell PG, Craig RW, Whyte MKB & Dockrell DH (2005) Dynamic changes in Mcl-1 expression regulate macrophage viability or commitment to apoptosis during bacterial clearance. J Clin Invest, 115(2), 359-368.
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