CR-PHAGOCYTOSIS · Complement-mediated phagocytosis in neutrophils
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2015-04-01 → 2017-03-31
- EU contribution
- €165,599
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
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Results in brief
Complement-mediated phagocytosis in neutrophils
The goal of this project is to understand how the complement system directs neutrophil phagocytosis of bacteria. The complement system is part of innate immunity that quickly becomes activated by pathogens, resulting in the production of “opsonin” molecules that label these target cells for recognition by phagocytic cells. During infection, neutrophils rapidly migrate toward target cells, and subsequently ingest and kill them. This process is critical for clearance of bacterial infections, but the underlying molecular mechanisms are not well understood, since these phenomena are often studied in complex physiological environments. Due to rapid rise in antibiotic-resistant bacteria, it is critical to explore alternative treatment strategies to handle bacterial infections in the near future. By understanding how immune cells (i.e. neutrophils) recognize and destroy bacteria, we could “guide” the complement system to tag these bacteria for destruction. Further, since complement-mediated phagocytosis is an important component of many immunotherapies, this information can be exploited to improve these treatments. The main objectives in this project include the development of tools to study complement opsonin-receptor interactions at a molecular level, to determine the role of complement opsonins in neutrophil uptake, activation and killing, and to study the collaborative action of antibodies and complement in neutrophil functioning.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- UNIVERSITAIR MEDISCH CENTRUM UTRECHT · UtrechtCoordinatorNetherlands
Links
- View on CORDIS
- DOI: 10.3030/659633
- http://web.archive.org/web/20170722225701/http://www.evasionutrecht.nl/themes/suzan-rooijakkers-bacteria-complement/
Data: CORDIS, © European Union