Team:Slovenia/Project/Motivation

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Revision as of 01:58, 30 October 2008

Motivation

The Goal – designer vaccine against Helicobacter pylori à la Synthetic biology

Response and sensing of the immune system is modular and activators of immune response are composed of discrete elements such as peptides, binding to the cellular receptors, bacterial or viral compounds that activate different cellular receptors that drive the polarization of immune response. Those stimulators that occur in different combinations in pathogenic microorganisms can be artificially combined into defined functional vaccines.

Modular approach of Synthetic biology can therefore offer powerful tools either based on bacteria as cell factories to produce advanced protein vaccines or to modify host cells by DNA vaccine in order to mount efficient immune protection.

An effective vaccine has to combine activation of the receptors of innate immunity and appropriate processing and presentation of antigens of a pathogen (see Background). Our idea was to combine antigens and activators of innate immune receptors into a single engineered molecule or gene construct. Bacteria H. pylori was selected as a target, to paraphrase JFK, “not because it is easy but because it is hard”. Its survival under harsh conditions and particularly avoidance of immune recognition (see Background) made it a formidable challenge and opportunity to try to outsmart it with tricks of synthetic immunology.

The Project idea

In order to achieve stimulation of innate immunity by proteins of H. pylori, which otherwise avoids immune recognition, we designed two tracks to prepare a high-tech vaccine:

Track 1: Engineered H. pylori flagellin-based vaccine

This type of engineered vaccine will be composed of different modules, each activating a selected arm of the immune response. Flagellin of H. pylori, which avoids activation of innate response receptor TLR5, will be engineered to regain activation of TLR5 and "become visible to the immune system", while it will retain the central most antigenic segment as a target of adaptive immune response. Additional immunobricks containing protein antigens and comprising several rationally selected epitopes will be added to increase the spectrum of proteins recognized by produced antibodies.

Track 2: Antigen-TLR fusion vaccine was designed to bypass the requirement of TLR agonists and provide the ability to trigger different signaling pathways or their combinations that result in antigen processing and presentation and production of a distinct set of costimulatory molecules. The main objective within this track was to prepare constructs with constitutively active Toll-like receptors that are:

· fused to antigens,

· localized within the activated endosomes,

· where antigen is processed into peptides that are loaded to MHC II or

· presented at cell surface to engage B-cell receptors while

· TLR activation additionally provides costimulatory signals to neighboring cells.

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