TRIM21: Antibody mediated anti-viral protection at mucosal surfaces
Infectious diseases kill more than twice as many people as cancer. While it is well recognized that antibodies patrol the extracellular space, a new mechanism shows that a virus or a bacterium coated with antibodies can be directed from outside the cell to the cytosol where the antibodies recruit an Fc binding receptor named tripartite-motif protein 21 (TRIM21). TRIM21 is an E3 ubiquitin ligase, and TRIM21 binding to the antibody-coated pathogen targets the complex for degradation - in a process that is dependent on the proteasome and unfolding machinery. The result is efficient neutralization and elimination of the pathogen before it has had time to replicate and spread. The mechanism is known as “antibody-dependent intracellular neutralization” (ADIN), and may have therapeutic utility.
Most infections occur at mucosal surfaces. Thus, it is important to understand how antibodies and TRIM21 operates in protection at mucosal barriers. The neonatal Fc receptor (FcRn) is expressed in the same tissue, and functions as a bidirectional transporter that carries antibodies of the IgG and immune complexes for delivery to lamina propria. Interestingly, FcRn interacts with the Fc part of IgG at a site that overlaps with the binding site for TRIM21. The aim of this study will be to gain new insights into how these receptors contribute to anti-viral immunity at both a molecular and a cellular level.
Methods: The student will gain experience in standard and advanced molecular techniques including sub-cloning of genes, DNA preparation, mutagenesis, cell culturing, cellular expression systems, protein purification, ELISA, Western blotting, antibody engineering and surface plasmon resonance-based determination of binding kinetics.
The work will be conducted in the Laboratory of Adaptive Immunity and Homeostasis headed by Jan Terje Andersen. The group is associated with the group of Inger Sandlie and the Centre for Immune Regulation (CIR):
The scientific goal of CIR is to identify mechanisms of immune dysregulation that contribute to autoimmune and allergic disease. Three models of autoimmune and allergic disease are studied in detail to identify novel mechanisms amenable to therapeutic intervention. Applying new information, we will develop and implement innovative agents for use in therapy. This work will involve a combination of basic research, research using animal and human disease models which will be carried out by the multidisciplinary Centre. The Centre is a collaborative of five research groups at the University of Oslo led by Oddmund Bakke, Bjarne Bogen, Frode Jansen, Inger Sandlie and Ludvig Sollid. Sollid is centre leader and Sandlie deputy leader. The Centre also brings in leading scientists from abroad. The CIR research activity is organized across groups, into 4 work packages, and Jan Terje Andersen is one of four work package coordinators, where the focus of his package is “Pathogenic and regulatory antibodies”.
Jan Terje Andersen, Oslo University Hospital, Division of Diagnostics and Intervention, Department of Immunology, Oslo University Hospital Rikshospitalet PO Box 4956 Nydalen NO-0424 Oslo, Norway. Tel: +47 23073773/+47 95159223 E-mail: firstname.lastname@example.org