Dr Britta Urban

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Areas of interest

Cellular immune responses to Plasmodium falciparum malaria; host-parasite interaction; immune-modulation by Variant Surface Antigens; function of dendritic cells in response to P. falciparum infected red blood cells.

Background

Britta Urban obtained a PhD at the Bernhard-Nocht Institute for Tropical Medicine in Hamburg, Germany in 1996, investigating complement resistance of Enatamoeba histolytica. She joined the David Roberts' laboratory at Oxford University on a Research Fellowship awarded by the German Research Council to study immune responses to Plasmodium falciparum malaria. She demonstrated that P. falciparum-infected erythrocytes modulate dendritic cell phenotype and function in vitro. These results formed the basis of a Wellcome Trust Career Development Fellowship where she investigated the role of dendritic cells in natural malaria infection in close collaboration with the KEMRI-Wellcome Trust Collaborative Programme in Kilifi, Kenya. She was awarded a Wellcome Trust Senior Research Fellowship in 2006 and has now moved with her group to Kilifi to study cellular immune responses to PfEMP-1. She is particularly interested to investigate whether the phenotypic properties of a given parasite isolate influence the immune response to that isolate.

Research

My research team investigates whether the phenotypic and antigenic properties of variant antigens expressed on the red cell surface of Plasmodium faciparum isolates determine cellular and humoral immune responses to that isolate.

Clinical immunity to Plasmodium falciparum bloodstage infection is related to exposure and to age, and occurs rapidly to severe disease, slower to mild disease and probably never to asymptomatic infection. However, at an age where children are most vulnerable to develop syndromes of severe disease, most children will harbour parasites but experience no or only mild clinical symptoms. The diversity of P. falciparum isolates is an important determinant of the heterogeneity in the phenotype of clinical malaria. Many targets of the humoral immune response are either polymorphic or undergo antigenic variation such as variant antigens expressed on the surface of infected red blood cells. Protective immune responses are associated with the ability to mount long-lived antibody responses to variant surface antigens expressed on "common" parasite isolates and the ability to mount to short-lived antibody responses during asymptomatic infection. However, in children with severe malaria, the relationship between parasite isolate, disease severity and host immune responses breaks down, suggesting that these children mount an inadequate antibody response. One family of variant proteins, the P. falciparum erythrocyte membrane protein-1 (PfEMP-1) mediates adhesion of bloodstage parasites to host cells and is central to both pathogenesis and protective immune responses. Cytoadhesion is an important determinant of organ-specific pathology in malaria but also results in the modulation of host cell function, both endothelial cells and dendritic cells. Adhesion of infected erythrocytes to CD36 modulates dendritic cell function in vitro and is positively correlated with the plasma concentration of IL-10 and inversely correlated with the plasma concentration of IL-12 in vivo. Dendritic cells initiate adaptive immune responses and control the deviation of T-cell responses. Therefore, the cytoadhesion phenotype of a given parasite isolate could influence the phenotype, duration and magnitude of adaptive T-cell and B-cell responses to that isolate.

Modern molecular typing techniques now permit to identify rapidly var genes encoding dominant expressed PfEMP-1 variants in a given isolate and allow for the first time to define cellular immune responses to that variant. My research group (Dr. Evelyn Gitau, James Tuju, Eva Kimani, Henry Karanje, Harry Fanjo) identifies the dominant-expressed PfEMP-1 variants using a method developed by Dr. Pete Bull and express a small part of the first domain, the DBL-a tag as a recombinant protein in E. coli. The recombinant protein is used to determine the proportion of CD4+ T cells that secrete IFNg, IL10 or both by 5-colour FACS in children with acute malaria and after convalescence. Ultimately, we want to define if and how the phenotypic and antigenic properties of a given parasite isolate shape the T-cell and B-cell responses that underlie the production of short-lived and long-lived antibodies against PfEMP-1.

In parallel, we (Eunice Nduati, Agnes Gwela) determine the phenotype and function of B cells in response to infected red blood cells using a in vitro activation assay and 5 colour FACS in healthy children and adults and in children with acute malaria and after convalescence. The aim of this study is to elucidate the defect that underlies the short-lived nature of antibody responses to many parasite antigens in children living in endemic areas

The entire team is based at the KEMRI-Wellcome Trust Collaborative Programme in Kilifi, Kenya. The Research Programme in Kilifi has a strong background in studies on the immuno-epidemiology of malaria. Our research links in with ongoing studies on cytoadhesion of infected red blood cells to endothelial cells (Dr Lucy Ocholla and Prof Alister Craig) and the immune-selection of var gene expression patterns in field isolates (Dr. Peter Bull).

Research Team

Top row left to right: Britta Urban, James Tuju, Eva Kimani
Middle row left to right: Evelyn Gitau, Harry Fanjo, Eunice Nduati
Bottom row left to right: Ceryl Andisi, Henry Karanje, Agnes Gwela

Current projects and grants

  • Wellcome Trust Senior Research Fellowship, Liverpool School of Tropical Medicine, UK and KEMRI/WTRL, Kilifi, Kenya; Cellular immune response in children with Plasmodium falciparum infection (2006-2011).
  • Wellcome Trust Programme grant to Kevin Marsh (PI), Pete Bull, James Beeson, Britta Urban, University of Oxford, UK and KEMRI/WTRL, Kilifi, Kenya. An integrated programme on the immuno-epidemiology of human blood stage immunity to P falciparum malaria (2005-2010).

Publications

  • Selected Publications

    Niederer HA, Willcocks LC, Rayner TF, Yang W, Lau YL, Williams TN, Scott JA, Urban BC, Peshu N, Dunstan SJ, Hien TT, Phu NH, Padyukov L, Gunnarsson I, Svenungsson E, Savage CO, Watts RA, Lyons PA, Clayton DG and Smith KG (2010). Copy number, linkage disequilibrium and disease association in the FCGR locus. Human Molecular Genetics [Epub ahead of print].

    Willcocks LC, Carr EJ, Niederer HA, Rayner TF, Williams TN, Yang W, Scott JA, Urban BC, Peshu N, Vyse TJ, Lau YL, Lyons PA and Smith KG (2010). A defunctioning polymorphism in FCGR2B is associated with protection against malaria but susceptibility to systemic lupus erythematosus. Proceedings of the National Academy of Sciences USA 107: 7881-7885.

    Todryk SM, Walther M, Bejon P, Hutchings C, Thompson FM, Urban BC, Porter DW and Hill AVS (2009).  Multiple functions of human T cells generated by experimental malaria challenge. European Journal of Immunology 39: 3042-3051.

    Todryk SM, Bejon P, Mwangi T, Plebanski M, Urban BC, Marsh K, Hill AV and Flanagan KL (2008). Correlation of memory T cell responses against TRAP with protection from clinical malaria, and CD4 CD25 high T cells with susceptibility in Kenyans. PLoS ONE 3: e2027.

    Clatworthy MR, Willcocks L, Urban BC, Langhorne J, Williams TN, Peshu N, Watkins NA, Floto RA and Smith KG (2007). Systemic lupus erythematosus-associated defects in the inhibitory receptor FcgammaRIIb reduce susceptibility to malaria. Proceedings of the National Academy of Sciences of the USA 104: 7169-7174.

    Cordery DV, Kishore U, Kyes S, Shafi MJ, Watkins KR, Williams TN, Marsh K and Urban BC (2007). Characterization of a Plasmodium falciparum Macrophage-Migration Inhibitory Factor Homologue. Journal of Infectious Diseases 195: 905-912.

    Urban BC, Cordery D, Shafi MJ, Bull P, Newbold CN, Williams TN and Marsh K (2006). The frequency of BDCA3+ dendritic cells is increased in the peripheral circulation of Kenyan children with severe malaria. Infection and Immunity74: 6700-6706.

    Ndungu F, Sanni L, Urban BC, Newbold CN, Marsh K and Langhorne J (2006). CD4 T cells from malaria-naive individuals respond to the CIDR1-a domain of Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP-1) via an MHC class II-T cell receptor-independent pathway. Journal of Immunology 176: 5504-5512.

    Urban BC, Mohamed JS, Cordery DV, Mwacharia A, Lowe B, Marsh K and Willams TN (2006). Reduced frequency of peripheral blood dendritic cells in healthy Kenyan children with a+thalassaemia. American Journal of Tropical Medicine and Hygiene 74: 578-584.

    Jenkins NE, Chakravorty SJ, Urban BC, Kai OK, Marsh K and Craig AG (2006). The effect of Plasmodium falciparum infection on expression of monocyte surface molecules. Transactions of the Royal Society for Tropical Medicine and Hygiene 100: 1007-1012.

    Horrocks P, Pinches RA, Papakrivos J, Chakravorty S, Christodoulou Z, Urban BC, Ferguson DJP and Newbold CI (2005). Efficient PfEMP1 export to the surface of Plasmodium falciparum infected erythrocytes appears to require the presence of knobs. Journal of Cell Science 118: 2507-2518.

    Urban BC, Hien TT, Day NP, Phu NH, Roberts R, Pongponratn E, Jones M, Mai NTH, Bethell D, Turner GDH, Ferguson D, White DJ and Roberts DJ (2005). Fatal Plasmodium falciparum malaria causes specific patterns of splenic architectural disorganisation. Infection and Immunity 73: 1986-1994.

    Ho L-P, Urban BC, Thickett DR, Davies RJO and McMichael A (2005). Deficiency of a subset of T-cells with immune-regulatory properties in sarcoidosis. The Lancet 365: 1062-1072.

    Ho L-P, Urban BC, Jones L, Ogg GS and McMichael AJ (2004). CD4-CD8alphaalpha subset of CD1d-restricted NKT cells controls T cell expansion. Journal of Immunology 172: 7350-7358.

    Leisewitz A, Rockett KA, Gumede B, Jones M, Urban BC and Kwiatkowski DP (2004). Response of the splenic dendritic cell population to malaria infection. Infection and Immunity 72: 4233-4239.

    Kojouharova M, Gadjeva MG, Tsacheva IG, Zlatarova A, Roumenina LT, Tchorbadjieva MI, Atanasov BP, Waters P,Urban BC, Sim RB, Reid KBM and Kishore U (2004). Mutational analysis of the recombinant globular regions of human C1q A, B and C chains suggest an essential role for the arginine and histidine residues in the C1q-IgG interaction. Journal of Immunology 172: 4351-4358.

    Kishore U, Gupta SK, Perdikoulis MV, Kojouharova MS, Urban BC and Reid KBM (2003). Modular organization of the carboxy-terminal, globular head region of human C1q A,B and C chains. Journal of Immunology 171: 812-820.

    Kishore U, Madan T, Sarma U, Singh M, Urban BC and Reid KBM (2002). Protective role of pulmonary surfactant proteins, SP-A and SP-D, against lung allergy and infection caused by Aspergillus fumigatus. Immunobiology 205: 610-618.

    Burthem J, Urban BC, Pain A and Roberts DJ (2001). The normal form of the human prion protein is strongly expressed in myeloid dendritic cells. Blood 98: 3733-3738.

    Urban BC, Mwangi T, Ross A, Kinyanjui S, Mosobo M, Kai O, Lowe B, Marsh K and Roberts D (2001). Peripheral blood dendritic cells in children with acute Plasmodium falciparum malaria. Blood 98: 2859-2861.

    Flanagan KL, Lee EAM, Gravenor MB, Reece WHH, Urban BC, Doherty T, Bojang KA, Pinder M, Hill AVS and Plebanski M (2001). Unique T-cell effector functions elicited by Plasmodium falciparum epitopes in malaria-exposed Africans tested by three T-cell assays. Journal of Immunology 167: 4729-4737.

    Urban BC, Willcox N and Roberts DJ (2001). A role for CD36 in the regulation of dendritic cell function. Proceedings of the National Academy of Sciences of the USA 98, 8750-8755.

    Pain A, Urban BC, Kai O, Casals-Pascuals C, Marsh K and Roberts DJ (2001). A non-sense mutation in Cd36 gene is associated with protection from severe malaria. Lancet 357: 1502-1503.

    Pain A, Ferguson DJP, Kai O, Urban BC, Lowe B, Marsh K and Roberts DJ (2001). Platelets mediated clumping ofP. falciparum infected erythrocytes is a common adhesive phenotype and is associated with severe disease.Proceedings of the National Academy of Sciences of the USA 98: 1805-1810.

    Urban BC, Ferguson D, Pain A, Plebanski M, Willcox N, Austyn J and Roberts DJ (1999). Plasmodium falciparum-infected erythrocytes modulate the maturation of dendritic cells. Nature 400: 73-77.

    Reviews
    Todryk SM and Urban BC (2008). Dendritic cells in Plasmodium infection. Review, Future Microbiology 3: 279-286.

    Urban BC and Todryk S (2006). Malaria pigment paralyzes dendritic cells. Minireview, Journal of Biology 5:4.

    Stevenson MM and Urban BC (2006). Antigen Presentation and Dendritic Cell Biology in Malaria. Invited Review,Parasite Immunology 28: 5-14.

    Ndungu F, Urban BC, Marsh K and Langhorne J (2005). Regulation of Malaria Immunity by Plasmodium falciparum-infected Red Blood Cells. Invited Review, Parasite immunology 27: 373-384.

    Urban BC, Ing R and Stevenson MM (2005). Early events in immunity to malaria. Review, Current Topics in Microbiology and Immunology 297: 25-97.

    Urban BC and Roberts DJ (2003). Inhibition of T cell function during malaria: implications for immunology and vaccinology. Comment, Journal of Experimental Medicine 107: 137-141.

    Urban BC and Roberts DJ (2002). Malaria, macrophages, monocytes and myeloid dendritic cells: sticking of infected erythrocytes switches host cells off. Review, Current Opinion in Immunology 14: 458-465.