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How antibodies and complement orchestrate protective immune responses against bacteria

Objective

Due to antibiotic resistance, there is now great interest in the development of antibody-based therapies against bacterial infections, for instance via antibodies that boost the host immune system. In order to kill bacteria, antibodies should trigger activation of the complement cascade, which forms bactericidal Membrane Attack Complex (MAC) pores and strongly enhances phagocytosis. Although the power of complement could be exploited for antibody therapies, such developments are hampered by our limited insights into the mechanisms underlying antibody-dependent complement activation on bacteria. My team has developed unique assays to study complement activation on bacteria. In this proposal, we will combine our function-driven approaches with novel B cell sequencing methods to identify anti-bacterial antibodies with strong complement-activating potential. We will develop novel approaches to identify the variable (VH:VL) sequences of human antibodies that recognize whole bacterial cells. After FACS sorting of memory B cells or yeast Fab display, we will use multi-well functional assays to select monoclonal antibodies driving potent complement activation and subsequent killing of E. coli (via neutrophils or MAC). Thanks to our unique tools and unprecedented insights, we are in an unique position to decipher basic mechanisms by which antibodies induce bacterial killing via neutrophils or MAC. We will combine live-cell imaging and structural approaches to determine how bactericidal antibodies assemble lethal MAC pores in the bacterial cell envelope. Finally, we will explore the design of potent antibody combinations and study the mechanisms by which antibodies steer different effector functions, both in the context of clinical and non-pathogenic E. coli strains. Altogether, this grant will lead to fundamental knowledge about the functioning of the immune system and provide a biological basis for the development of antibody-based therapies against bacteria.

Field of science

  • /natural sciences/biological sciences/microbiology/bacteriology
  • /medical and health sciences/basic medicine/pharmacology and pharmacy/drug resistance/antibiotic resistance
  • /medical and health sciences/basic medicine/immunology

Call for proposal

ERC-2020-COG
See other projects for this call

Funding Scheme

ERC-COG - Consolidator Grant

Host institution

UNIVERSITAIR MEDISCH CENTRUM UTRECHT
Address
Heidelberglaan 100
3584 CX Utrecht
Netherlands
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 2 000 000

Beneficiaries (1)

UNIVERSITAIR MEDISCH CENTRUM UTRECHT
Netherlands
EU contribution
€ 2 000 000
Address
Heidelberglaan 100
3584 CX Utrecht
Activity type
Higher or Secondary Education Establishments