Dynamics of bacterial killing by the membrane attack complex

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To avoid the spreading of bacteria in the blood stream, our immune system contains the so-called complement system, a large arsenal of proteins that collectively promote inflammation and target microbes. One of complement's rather spectacular functions is that of piercing the membranes of Gram-negative bacteria such as E. coli, thus killing the bacteria. In some cases, we may wish to enhance this immune function, for example to counter bacterial infections; in other cases, such as sepsis, it may be beneficial to prevent a patient's overactive immune system from causing potentially lethal effects. For the development of any such therapeutic approaches, it helps to have a sound understanding of how complement works.In this project, we focus on the membrane attack complex, used by complement to form pores in the membranes of bacteria. So far, many structural and functional studies have been carried out on the MAC attacking single-membrane model systems such as lipid vesicles and red blood cells. However, the envelope of Gram-negative bacteria consists of a double membrane with a mesh-like peptidoglycan layer in between. At present, it is not clear how the MAC overcomes this triple barrier. To address this question, we will use a special type of microscopy, atomic force microscopy, in which a sharp needle can trace the surface of a bacterium as it is being attacked by the MAC. Briefly, by thus visualising the formation of MAC on the bacterial surface and the subsequent effects on the bacterial envelope, we will determine the mechanisms by which the MAC kills bacteria.