Sub-project 2

CISBIC Sub-project 2: Spatio-temporal Control of Phagocytic Signalling During Uptake of Attenuated Salmonella typhimurium

Recognition and uptake of bacteria, parasites and encapsulated DNA vaccines by professional phagocytes - macrophages, dendritic cells - is crucial for the induction of protective immunity, through cytokine release and processing and presentation of antigens for recognition by the adaptive immune system. Live attenuated strains of intracellular pathogens such as Salmonella and Shigella have been shown to act as oral human and animal vaccines and as heterologous vaccine carriers capable of inducing protective responses to antigens from other viral, bacterial and eukaryotic pathogens.

The mechanism of attenuation is crucial in determining vaccine efficacy, but the biology of this is unknown; in practice multiple mutants are screened in an empirical trial and error manner. It would be a major scientific advance to be able to engineer improved vaccine strains on the basis of a rational understanding of the factors that determine their ability to stimulate a protective, lasting immune response. This may now be possible through a systems biology approach that can directly inform on logical targets for mutagenesis studies. Because interaction with innate immune cells is central to immunogenicity, in this sub-project we will study the early stages of phagocytosis of attenuated Salmonella typhimurium and develop predictive models that will assist in design of improved human and animal vaccines.

Organisms:

  • Salmonella typhimurium

Funding:

Affiliates:

For more information about the outputs from this project or to discuss data reuse please contact bsshelp@imperial.ac.uk

CISBIC Sub-project 2

Project Members

  • Dr Robert Endres
  • Dr Emmanuelle Caron
  • Dr George Tzircotis (biology)
  • Dr Ozan Kahramanoğulları (modelling)
  • Dr Jeroen van Zon (modelling)
  • Dr Anna Dart (biology)
  • Dr Sylvain Tollis (modelling)
  • Dr Amir Horowitz (biology)
  • Dr Martin Spitaler (core facility)
  • Dr Vania Braga (biology)
  • Dr Martin Howard (modelling)

Software

PIM-SPiM: An Intuitive Automated Modelling Interface for Systems Biology (Kahramanoğulları)

This tool performs automated translation of models of biochemical systems written in a natural language-like syntax into a program in Microsoft Research's stochastic simulation language (SPiM) for π calculus

Models

  • Image analysis (Tollis)
    MATLAB code for the analysis of microscopy images of bacterial phagocytosis
  • Simulations (Tollis)
    Surface Evolver code for the simulation of bacterial phagocytosis
  • Actin models and their graphical visualization (Kahramanoğulları)
    Compositional process algebra models of actin polymerisation and a geometric representation of these models that allows movies to be generated reflecting their dynamics
  • Stochastic π calculus model of phagocytosis (Kahramanoğulları)
    PIM model and corresponding SPiM representation of Fcγ receptor phosphorylation during phagocytosis (from http://dx.doi.org/10.4204/EPTCS.9.9)

Datasets

Publications

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