Objective Complement-mediated phagocytosis plays a crucial role in bacterial killing. Activation of complement yields a variety of opsonin molecules that can rapidly coat bacterial surfaces, which interact with complement receptors on neutrophils to facilitate phagocytosis. However the molecular details and functional outcomes of these interactions are not well understood. In the proposed work, we aim to elucidate the molecular details of complement opsonin-receptor interactions. We have developed a novel model for examining molecular complement interactions, by site-specifically attaching complement opsonins to bacteria-sized beads in their correct orientation. We will, for the first time, be able to adequately characterize complement opsonin-receptor interactions at a molecular level. This methodology will also be extended to two model gram-positive bacteria, Staphylococcus aureus (S. aureus) and Group B Streptococcus (GBS), in which complement opsonins will be site-specifically attached to their cell walls. Using wild-type and complement receptor (CR) knockdown neutrophils, we aim to determine the roles of opsonin-receptor pairs in neutrophil activation and bacterial killing. Finally, we will use our model systems to examine the synergy between antibodies and complement in neutrophil phagocytosis. The proposed work will provide a comprehensive picture of the role of complement in neutrophil phagocytosis. As the role of complement in human disease is becoming increasingly apparent, the need for new therapeutics is imminent. The work proposed herein paves the way for several therapeutic applications, including targeted complement-dependent cytotoxicity (CDC) immunotherapeutics in cancer and complement inhibitors for a wide array of age-related, autoimmune, and rare/neglected disorders. Fields of science natural sciencesbiological sciencesmicrobiologybacteriologymedical and health scienceshealth sciencesinfectious diseasesmedical and health sciencesclinical medicineoncologymedical and health sciencesbasic medicineimmunologyimmunotherapynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2014-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF) Call for proposal H2020-MSCA-IF-2014 See other projects for this call Funding Scheme MSCA-IF-EF-ST - Standard EF Coordinator UNIVERSITAIR MEDISCH CENTRUM UTRECHT Net EU contribution € 165 598,80 Address HEIDELBERGLAAN 100 3584 CX Utrecht Netherlands See on map Region West-Nederland Utrecht Utrecht Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 165 598,80
