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Molecular and cellular imaging of membrane interactions in pathogen attack and immune defense

Objective

"The immune system and pathogens both use membrane pore-forming proteins to penetrate cellular membranes, in order to kill target cells or to allow passage of pathogenic organisms such as malaria parasites, listeria, or toxoplasma. For both fundamental and practical reasons, it is important to understand the biological actions of the ""arms race"" underlying virulence, pathogenesis and immune defense. The key weapon in this membrane attack is a class of proteins that upon activation undergo a dramatic conversion from water-soluble monomers to a large, membrane-inserted assembly. Both the human immune response and microbial pathogenesis rely on membrane disruption by perforin-like proteins for attack and counterattack. This protein superfamily encompasses perforin and complement pore-forming assemblies in the immune system, as well as the more distantly related bacterial cholesterol-dependent cytolysins. With recent advances in electron cryo-microscopy, tomography and correlative fluorescence microscopy, it is now possible to relate the workings of protein machines in model systems such as liposomes to their actions in the cellular context. I wish to capitalize on these technical advances and visualize membrane interactions at the moment the intracellular pathogen Toxoplasma gondii bursts out of its host cell, as well as the delivery of lethal cargo from the cytotoxic lymphocyte to its target cell through the immune synapse. These studies will correlate 3D spatial information at cellular and molecular levels to reveal the operation of dynamic cellular machinery. I have chosen a well-ordered system that can bridge the gulf between cell biology and atomic structure. Innovations in sample preparation combined with state-of the art imaging methods will lead to the molecular definition of a fundamental process in “hostile” communication between cells and will broaden the landscape for drug design for immune disorders and major infectious diseases."

Field of science

  • /medical and health sciences/health sciences/public and environmental health/epidemics prevention/immunisation
  • /medical and health sciences/basic medicine/medicinal chemistry
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /natural sciences/biological sciences/cell biology
  • /medical and health sciences/basic medicine/immunology

Call for proposal

ERC-2011-ADG_20110310
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

BIRKBECK COLLEGE - UNIVERSITY OF LONDON
Address
Malet Street
WC1E 7HX London
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 2 311 036
Principal investigator
Helen Saibil (Prof.)
Administrative Contact
Juan Vidal (Mr.)

Beneficiaries (1)

BIRKBECK COLLEGE - UNIVERSITY OF LONDON
United Kingdom
EU contribution
€ 2 311 036
Address
Malet Street
WC1E 7HX London
Activity type
Higher or Secondary Education Establishments
Principal investigator
Helen Saibil (Prof.)
Administrative Contact
Juan Vidal (Mr.)