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.
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.
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).
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).