Profile

Career

Research

Overview

• Antigen presentation
• Immunopathology
• Leishmaniasis
• Dendritic cells
• Imaging
• Inflammation
• Macrophages

Paul's laboratory continues to focus on antigen presenting cells (APC), with a particular emphasis on the temporal and tissue-specific changes that occur in the APC compartment during the progression of inflammatory and infectious disease. Although experimental models of visceral leishmaniasis provide the major context in which these studies are performed, the laboratory has more recently introduced other infectious and non-infectious models to complement and extend these studies. Ongoing projects span fundamental research into macrophage and dendritic cell development, heterogeneity and function, and translational projects aimed at taking this knowledge forward for the development of new therapeutic tools and vaccines.

Technologies

2-photon intravital microscopy, immuno-histochemistry, gene expression profiling

Current projects

• Immunopathology, stromal cell function and immune regulation
  In experimental models of visceral leishmaniasis, parasites can be found in multiple systemic organs, but control of parasite burden is tissue-specific. In the liver, granulomatous inflammation provides the means for parasite containment and eventual elimination. In contrast, the spleen undergoes tremendous enlargement, accompanied by extensive remodeling of tissue architecture and parasite persistence. These diverse settings provide unique opportunities to examine how microenvironment affects APC differentiation and function. Current projects include: the function and fate of marginal zone macrophages; the role of DC cytokine production in regulatory T cell differentiation; the role of angiogenesis in splenic tissue remodeling; immunotherapeutic applications of costimulatory molecule blockade.
• Macrophage and dendritic cell heterogeneity
  Macrophages and dendritic cells show considerable tissue specific diversity in form and function. Active research projects in this area include: gene expression profiling of tissue macrophage subsets and their response to Leishmania infection; the role of Irf-7 in regulating macrophage function; immunoregulatory and migratory capacity of alveolar and LN resident macrophages.
• Reproductive tract immunology
  With Charles Lacey, we are conducting comparative studies of the human and rodent female genital tract, as a means to inform the development of new microbicides and vaccines for sexually transmitted infections (inc. HIV) and to develop new in vitro organotypic assays for candidate drug screening. Current laboratory projects include a study of the role of FcRn in IgG transport and research on the heterogeneity and regulation of vaginal DC. These studies complement ongoing clinical trials of new microbicides and vaccines with the HIV EUROPRISE Network.
• Development of novel immune potentiators
  In collaboration with Dianna Bowles and Jack Lim in the Centre for Novel Agricultural Products, we are using a novel platform of recombinant glycosyltransferases derived from Arabidopsis thaliana to regiospecifically modify a variety of small molecule scaffolds with known activity on dendritic cells.
  Using this technology, in conjunction with high content screening approaches, we aim to develop novel adjuvants and immunotherapeutics with fine-tuned activity profiles.
• Therapeutic vaccines for visceral leishmaniasis
  Our studies in experimental visceral leishmaniasis indicate that (re-)activation of CD8+ T cells responses may provide synergy with chemotherapy in the treatment of human disease. With funding from a Wellcome Trust Translation Award, we are progressing these studies through their final pre-clinical stages, with the aim of conducting a first-in-man trial in UK volunteers in late 2010.

Research group(s)

• Kaye research group (Experimental medicine, Immunology)

Grants

• Wellcome Trust Translational Award
  Co-PI, with Walden and Lacey, 'Therapeutic CD8+ T cell-biased vaccines for human visceral leishmaniasis' 01/10/08 - 31/12/11
• Wolfson Foundation
  PI, with Lacey and Smith, 'Development of the Wolfson Laboratories in the Centre for Immunology and Infection' 
• MRC Programme Grant
  PI, "Immunology and Immunopathology of Visceral Leishmaniasis" 01/01/11 - 31/12/15
• Wellcome - Wolfson Foundation Infrastructure Award
  Centre for Hyperpolarisation in MRI, co-application with Duckett & Green (PIs)
  

Available PhD research projects

Intracellular parasitism of stromal cells (for 2012 - 13)

Intracellular bacterial and protozoal pathogens, responsible for some of the major global infectious diseases of man, are known to be able to reside and multiply within stromal cells, and it has been suggested that stromal cells may provide a safe target, being restricted in their anti-microbial properties.  Infection of stromal cells also accompanies remodelling of SLO microarchitecture, suggesting pathogens may subvert stromal cell function in the maintenance of tissue architecture. Stromal cells also support local haematopoiesis during infection, another function altered by intracellular infection. In this project, we will mine existing gene expression data derived from murine and human stromal cell lines infected with L. donovani (the causative agent of visceral leishmaniasis) and use bioinformatic approaches to identify transcription factors associated with genes differentially regulated as a direct consequence of infection.  Functional validation of the importance of these TFs will be obtained by expression profiling of target gene knock-down cell lines (generated using established shRNA approaches) and by conventional EMSA analysis. The impact of gene knock-down on parasite intracellular survival will be evaluated using standard parasitological techniques, flow cytometry and confocal microscopy.  Targets evaluated in this way will also provide a focus for studies on the in vivo manipulation of stromal cells during infection, with an emphasis on pathways that may regulate fibrosis.

Please email paul.kaye@york.ac.uk for further enquiries.

For application requirements, process, and guidelines please see the postgraduate study pages of the Department of Biology website (http://www.york.ac.uk/biology/postgraduate/). New available studentships are announced on these web pages, the Departmental site and on FindAPhD.

Publications

Full publications list

• Yurdakul P, Dalton J, Beattie L, Brown N, Erguven S, Maroof A, Kaye PM. Compartment-Specific Remodeling of Splenic Micro-Architecture during Experimental Visceral Leishmaniasis. (2011) Am J Pathol. 2011 Jul;179(1):23-9. Epub Apr 30.
• McFarlane E, Carter KC, McKenzie AN, Kaye PM, Brombacher F, Alexander J.  Endogenous IL-13 plays a crucial role in liver granuloma maturation during Leishmania donovani infection, independent of IL-4Rα-responsive macrophages and neutrophils. (2011) J Infect Dis. Jul;204(1):36-43.
• Beattie L, Phillips R, Brown N, Owens BM, Chauhan N, Dalton JE, Kaye PM. Interferon regulatory factor 7 contributes to the control of Leishmania donovani in the mouse liver. (2011) Infect Immun. Mar;79(3):1057-66. Epub 2010 Dec 13.
• Working Group on Research Priorities for Development of Leishmaniasis Vaccines, Costa CH, Peters NC, Maruyama SR, de Brito EC Jr, Santos IK. Vaccines for the leishmaniases: proposals for a research agenda. (2011) PLoS Negl Trop Dis. Mar 29;5(3):e943.
• Kaye, PM, Scott P. Leishmaniasis: complexity at the host-pathogen interface. (2011) Nat Rev Microbiol. Jul 11;9(8):604-15. doi: 10.1038/nrmicro2608.
• Dalton JE, Kaye PM. Immunomodulators: use in combined therapy against leishmaniasis. (2010) Expert Rev Anti Infect Ther. Jul;8(7):739-42.
• Nguyen Hoang AT, Liu H, Juarez J, Aziz N, Kaye PM, Svensson M. (2010) Stromal Cell-Derived CXCL12 and CCL8 Cooperate to Support Increased Development of Regulatory Dendritic Cells following Leishmania Infection. J Immunol 185:2360-71.
  
• de Souza JB, Okomo U, Alexander ND, Aziz N, Owens BMJ, et al. 2010 Oral Activated Charcoal Prevents Experimental Cerebral Malaria in Mice and in a Randomized Controlled Clinical Trial in Man Did Not Interfere with the Pharmacokinetics of Parenteral Artesunate. PLoS One 5(4): e9867
• Dalton JE, Maroof A, Owens BM, Narang P, Johnson K, Brown N, Rosenquist L, Beattie L, Coles M, Kaye PM. (2010) Inhibition of receptor tyrosine kinases restores immunocompetence and improves immune-dependent chemotherapy against experimental leishmaniasis in mice. J Clin Invest. Apr 1;120(4):1204-16.
• Beattie L, Peltan AP, Maroof A, Kirby A, Brown N, Coles M, Smith DF and Kaye PM. (2010) Dynamic imaging of experimental Leishmania donovani-induced hepatic granulomas detects Kupffer cell-restricted antigen presentation to antigen-specific CD8+ T cells. PLoS Pathog. Mar 12;6(3):e1000805 
• Phillips R, Svensson M, Aziz N, Maroof A, Brown N, Beattie L, Signoret N and Kaye PM. (2010) Innate killing of Leishmania donovani by macrophages of the splenic marginal zone requires IRF-7 PLoS Pathog. Mar 12;6(3):e1000813.
• Maroof A, Beattie L, Kirby A, Coles M, Kaye PM. (2009) Dendritic cells matured by inflammation induce CD86-dependent priming of naive CD8+ T cells in the absence of their cognate peptide antigen. J Immunol. Dec1;183(11):7095-103.
• Beattie L, Svensson M, Bune A, Brown N, Maroof A, Zubairi S, Smith KR, Kaye PM. (2009) Leishmania donovani-induced expression of signal regulatory protein alpha on Kupffer cells enhances hepatic invariant NKT-cell activation. Eur J Immunol. Oct 28;40(1):117-123.
• Rowe HM, Lopes L, Brown N, Efklidou S, Smallie T, Karrar S, Kaye PM, Collins MK (2009) Expression of vFLIP in a lentiviral vaccine vector activates NF-KB, matures dendritic cells and increases CD8+ T cell responses. J Virol, 83: 1555-62
  
• Kirby AC, Beattie L, Maroof A, van Rooijen N, Kaye PM (2009) SIGNR1-negative red pulp macrophages protect against acute streptococcal sepsis after Leishmania donovani-induced loss of maringal zone macrophages Am J Pathol, Sep;175(3):1107-15
• Kirby AC, Coles MC, Kaye PM, (2009) Alveolar macrophages transport pathogens to lung draining lymph nodes Journal of Immunology Aug 1;183(3):1983-9
• Depledge DP, Evans KJ, Ivens AC, Aziz N, Marroof A, Kaye PM, Smith DF (2009) Comparative Expression Profiling of Leishmania: Modulation in Gene Expression between Species and in Different Host Genetic Backgrounds PLoS Negl Trop Dis, Jul 7:3(7):e476
• D. Schonfeld, G. Matschiner, L. Chatwell, S. Trentmann, H. Gille, M. Hulsmeyer, N. Brown, P.M.Kaye (2009) An engineered lipocalin specific for CTLA-4 reveals a combining site with structural and confrontational features similar to antibodies PNAS, May 5, doi: 10.1073/pnas.0813399106
• Flugge AJ, Timmis J, Andrews P, Moore J, Kaye PM (2009) Modelling and Simulation of Granuloma Formation in Visceral Leishmaniasis. Congress on Evolutionary Computation (CEC) pp 3052-59. IEEE Press
  
• Stanley, A., Dalton JE., Rossotti, S., MacDonald, K., Zhou, Y., Rivera, F., Schroder, W., Maroof, A., Hill, GR., Kaye, P., and Engwerda, C. (2008) VCAM-1 and VLA-4 Modulate Dendritic Cell IL-12p40 Production in Experimental Visceral Leishmaniasis PLoS Pathog. September 4(9): e1000158
• Maroof, A., Beattie, L., Zubairi, S., Svensson, M., Stager, S., and Kaye, P.M. (2008) Post-transcriptional regulation of IL-10 gene expression allows NK cells to express immunoregulatory function. Immunity, Volume 29, Issue 2, 295-305
• Maroof A, and Kaye PM. (2008) Temporal regulation of interleukin-12p70 (IL-12p70) and IL-12-related cytokines in splenic dendritic cell subsets during Leishmania donovani infection. Infect Immun. 76:239-49
• Beattie L, Evans KJ, Kaye PM, and Smith DF. (2008) Transgenic Leishmania and the immune response to infection. Parasite Immunol. 30:255-66
• Moreno, J., J. Nieto, S. Masina, C. Cañavate, I. Cruz, C. Chicharro, E. Carrillo, S. Napp, C. Reymond, P. M. Kaye, D. F. Smith, N. Fasel, and J. Alvar. (2007) Immunization with H1, HASPB1 and MML Leishmania proteins in a vaccine trial against experimental canine leishmaniasis. Vaccine, Jul 20;25(29):5290-300.
• Radwanska M, Cutler AJ, Hoving JC, Magez S, Holscher C, et al. (2007) Deletion of IL-4Ra on CD4 T Cells Renders BALB/c Mice Resistant to Leishmania major Infection. PLoS Pathog 3(5): e68 doi:10.1371/journal.ppat.0030068
• Kirby A, Newton D, Carding S, Kaye P. (2007) Pulmonary dendritic cells and alveolar macrophages are regulated by gammadelta T cells during the resolution of S. pneumoniae-induced inflammation. J Pathol. 212:29-37
• Kirby, A, Newton, D, Carding S, Kaye P (2007) Evidence for the involvement of lung-specific gammadelta T cell subsets in local responses to Streptococcus pneumoniae infection. Eur J Immunol. December; 37(12): 3404-3412
• Svensson M, Kaye PM. (2006) Stromal-cell regulation of dendritic-cell differentiation and function. Trends Immunol. 27:580-587.
• Stager, S., Maroof, A., Zubairi, S., Sanos S.L., Kopf, M, Kaye, P.M. (2006) Distinct roles for IL-6 and IL-12p40 in mediating protection against Leishmania donovani and the expansion of IL-10(+) CD4(+) T cells Eur J. Immunol 36:1764-71
• Hassan, M.F., Zhang, Y., Engwerda, C.R., Kaye, P.M., Sharp, H. and Bickle, Q.D. (2006) The Schistosoma mansoni hepatic egg granuloma provides a favourable micro-environment for sustained growth of Leishmania donovani Am. J. Path. 169(3):943-53
  
• Gray, P.M., Reiner, S.L., Smith, D.F., Kaye, P.M. and Scott, P. (2006) Antigen-experienced T cells limit the priming of naive T cells during infection with Leishmania major. J. Immunol. 177: 925-933
• Kirby, A.C., Raynes, J.G. and Kaye, P.M. (2006) CD11b regulates recruitment of alveolar macrophages but not pulmonary dendritic cells following pneumococcal challenge. J. Infect. Dis. 193:205-13
• Ato, M., Maroof, A., Zubairi, S., Nakano, H., Kakiuchi, T. and Kaye, P.M. (2006) Loss of dendritic cell migration and impaired resistance to L. donovani infection in mice deficient in CCL19 and CCL21. J. Immunol 176:5486-5493
• Polley, R., Sanos, S.L., Prickett, S., Haque, A. and Kaye, P.M. (2006) Adoptive Immunotherapy against Experimental Visceral Leishmaniasis with CD8+ T Cells Requires the Presence of Cognate Antigen. Infect. Immun. 74:773-776
• Prickett, S., P.M. Gray, S.L. Colpitts, P. Scott, P.M. Kaye, D.F. Smith. (2006) In vivo recognition of ovalbumin expressed by transgenic Leishmania is determined by its subcellular localization. J Immunol., 176:4826-4833
• Polley, R., Sanos, S.L., Prickett, S., Haque, A. and Kaye, P.M. (2005)
Chronic Leishmania donovani infection promotes bystander CD8+ T cell expansion and heterologous immunity. Infect. Immun 73: 7996-8001
• Kirby, A.C., Raynes, J. G. and Kaye, P. M. (2005) CD11b regulates recruitment of alveolar macrophages but not pulmonary dendritic cells following pneumococcal challenge J. Infect. Dis. 193:205-13
• Svensson, M., Zubairi, S., Maroof, A., Kazi, F., Taniguchi, M. and Kaye, P. M. (2005) Invariant NKT cells are essential for the regulation of hepatic CXCL10 gene expression during Leishmania donovani infection Infect. Immun. 73: 7541-7547
• Rafati, S., Nakhaee, A., Taheri, T., Taslimi, Y., Darabi, H., Eravani, D., Sanos S., Kaye, P.M., Taghikhani, M., Jamshidi, S. and Ali Rad, M. (2005) Protective vaccination against experimental canine visceral leishmaniasis using a combination of DNA and protein immunization with cysteine proteinases type I and II of L. infantum Vaccine 23: 3716-3725
• Kirby, A.C., Raynes, J.G. and Kaye, P.M. (2005) The role of TNF in localized and systemic infection with Streptococcus pneumoniae J. Infect. Dis 191:1538-1547.
• Svensson, M., Maroof, A., Ato, M. and Kaye, P.M. (2004) Stromal cells direct local differentation of regulatory dendritic cells Immunity 21:805-816
• Polley, R., Zubairi, S. and Kaye, P.M. (2005) The fate of the heterologous CD4+ T Cells during Leishamani donovani infection. Eur. J. Immunol. 35: 498-504
• Ato, M., Nakano, H., Kakiuchi, T. and Kaye, P.M. (2004) Localisation of marginal zone macrophages is regulated by CCL19/CCL21. J. Immunol 173: 4815-4820
• Engwerda, C.R., Ato, M., Stager, S., Alexander, C. E. and Kaye, P.M. (2004) Distinct roles for lymphotoxin-a and TNF in the control of Leishmania donovani infection Am. J.Path 165: 2123-2133
• Zubairi, S., Sanos A., Hill, S. and Kaye, P.M. (2004) Immunotherapy with OX40L-Fc or anti-CTLA-4 enhances local tissue responses and killing of Leishmania donovani. Eur.J. Immunol 34: 1433-1440
• Engwerda, C.R., Ato, M. and Kaye, P.M. (2004) Macrophages, pathology and parasite persistance in experimental visceral leishmaniasis. Trends. Parasitol. 20: 524-530
• Stager, S. and Kaye, P.M. (2004) CD8+ T cell priming regulated by cytokines of the innate immune system. Trends Mol. Med. 10:366-371
• Kaye, P.M., Svensson, M., Ato, M., Maroof, A., Polley, R., Stager, S., Zubairi, S. and Engwerda, C. R. (2004) The immunopathology of experimental visceral Leishmaniasis. Immunol. Rev. 201: 239-253
• Stager, S., Alexander, J., Botto, M., Kirby, A.C., Van Rooijen, N., Smith, D.F., Brombacher, F. and Kaye, P.M. (2003) Natural antibodies and complement are endogenous adjuvants for vaccine-induce CD8+ T cell responses. Nature Medicine 9:1287-1292
• Stager, S., Alexander, J., Carter, K.C., Brombacher, F. and Kaye, P.M. (2003) Both Interleukin-4 (IL-4) and IL-4 Receptor Signaling Contribute to the Development of Hepatic Granulomas with Optimal Antileishmanial Activity Infect Immun. 71:4804-4807
• Meier, C.L., Svensson, M. and Kaye, P.M. (2003) Leishmania-induced inhibition of macrophage antigen presentation analysed at the single cell level. J.Immunol. 171:6706-6713
• Quinnell, R.J., Courtenay, O., Garcez, L.M., Kaye, P.M., Shaw, M.A., Dye, C., and Day, M.J. (2003) IgG subclass responses in a longitudinal study of canine visceral leishmaniasis. Veterinary Immunology and Immunopathology 91:161-168
• Davies, C.R., Kaye, P.M., Croft, S.L., and Sundar, S. (2003) Leishmaniasis: New approaches to disease control B.M.J. 326:377-382
• Kaye, P.M. and Engwerda, C.R. (2003) Murine leishmaniasis In Granulomatous Inflammation and Infection. D. Boros Ed ASM Press USA 117-146
• Sher, A., Pearce, E. and Kaye, P.M. (2003) Shaping the immune response to parasites: role of dendritic cells. Curr. Opin Immunol. 15: 421-429
• Ato, M., Stager, S., Engwerda, C.R. and Kaye, P.M. (2002) Defective CCR7-dependent migration of dendritic cells contributes to the development of chronic visceral leishmaniasis. Nature Immunology 3: 1185-1191
• Engwerda, C.R., Ato, M., Cotterell, S. E., Mynott, T.L., Tschannerl, A., Gorak-Stolinska, P.M.A. and Kaye, P.M. (2002) A role for tumor necrosis factor-alpha in remodeling the splenic marginal zone during Leishmania donovani infection. Am. J. Path 161:429-437
• Engwerda, C.R., Mynott, T.L., Sawhney, S., De Souza, J.B., Bickle, Q.D. and Kaye, P.M. (2002) Locally up-regulated lymphotoxin alpha, not systemic tumor necrosis factor alpha, is the principle mediator of murine cerebral malaria. J. Exp. Med 195:1371-1377
• Kaye, P.M. (2002) The immunology of visceral leishmaniasis: current status. In World Class Parasites: Vol 4 Leishmania. J.P. Farrell Ed Kluwer Academic Publishers pp137-150
• Kelsall, B.L., Biron, C.A., Sharma, O. and Kaye, P.M. (2002) Dendritic cells at the Host-Parasite interface (Conference report). Nature Immunology 3:699-702
• Alexander, C., Kaye, P.M. and Engwerda, C.R. (2001) CD95 is required for the control of murine visceral leishmaniasis caused by L. donovani infection. Eur. J. Immunol. 31:1199-1210
• Babaloo, Z., Kaye, P.M. and Eslami, M.B. (2001) IL-13 in Iranian patients with visceral leishmaniasis: relationship to other Th2 and Th1 cytokines. Trans. Roy. Soci. Trop. Med. Hyg. 95:85-88
• Quinnell, R.L.J., Courtney, O., Shaw, M-A., Day, M.J., Garcez, L., Dye, C. and Kaye, P.M. (2001) Tissue cytokine response in canine visceral leishmaniasis. J. Infect. Dis. 183:1421-1424
• Kaye, P.M. (2001) Analysis of antigen processing and presentation. In Macrophage Methodology: A Practical Approach. Paulnock, d. Ed Oxford University Press, Oxford, UK pp 93-113
• Kaye, P.M. (2000) Granulomatous diseases. Int J Exp Path 81:289-90
  

External activities

Memberships

• British Society for Immunology
  Member
• Pathological Society of Great Britain and Ireland
  Member
• Royal College of Pathologists
  Fellow