Ljubljana, Slovenia 2006/Project
Although in the past years all participating iGEM teams focused on bacteria and yeast, we decided to modify signalling pathways in higher eukaryotes. This is a far more complicated system to understand but we feel that the recently accumulated knowledge enables rational planning of cells with novel properties.
When bacteria attack a human body, immune response is the normal reaction of the organism. Cells which represent the first line of defence are macrophages and the way they act is rather complicated. On the surface of these cells (actually inserted into cell membrane) are several types of receptor molecules, commonly abbreviated as TLR (toll-like receptors). These can specifically bind various components of bacteria (e.g. lipopolysaccharides which are part of bacterial outer membranes) and upon binding, they interact with other molecules inside the cell, forming a cell signalling pathway that, after several relays, ends in the cell nucleus and induces production of immune response proteins, such as cytokines and chemokines. The complete pathway is depicted here and is rather complicated. Stages of the signal transfer were elucidated recently. Cell signalling like this is the basis of our efficient innate immune response (i.e. the fast-acting, not mediated by antibodies) against microbes. In some instances, however, signalling mediated by TLR is not beneficial. Under some not yet fully understood circumstances, bacteria can trigger this same signalling pathway just that it results in excessive inflammatory response. As result, sepsis occurs, which can lead to severe organ failure and in about 20% cases cosequences are fatal.
After binding of bacterial constituents to TLR, its intracellular TIR-domain interacts with either MyD88 or TRIF, two signalling molecules in the cytoplasm that relay signal to other components of the pathway as shown here.
(more to follow)