Capturing functional states of type III secretion systems from Chlamydia in situ

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Many 'friendly' bacteria live passively in the environment or engage in beneficial associations with plants and animals, for example by fixing nutrients or assisting digestion. Other bacteria have gained the ability to live inside more complex organisms where they survive and multiply. Although able to expend these 'host' organisms for their own advantage, these aggressive bacteria also cause damage to the host, which results in disease. Doctors have treated such bacterial infections in man and animals with antibiotics, yet recently bacteria are increasingly developing resistance to these drugs. Consequently, it is crucial to understand how different bacteria cause disease at a molecular level, as this will provide clues to new ways to treat patients and develop vaccines. It has emerged that many of these bacteria deploy a sophisticated weapon that acts like a minute syringe to inject host cells with a cocktail of bacterial proteins called 'effectors'. An important focus of current biomedical research is to decipher how these syringes and effectors operate.One of these disease-causing bacteria called Chlamydia is responsible for serious infections. It is the main bacterial cause of sexually transmitted disease and infertility in the U.K. and other developed countries, and of a widespread form of blindness called 'trachoma', which is designated as a neglected tropical disease by the World Health Organisation. It is very challenging to study Chlamydia in the laboratory as they cannot grow outside host cells at all. Chlamydia use a molecular syringe to deliver effectors that enable the bacteria to force their own entry into host cells and to replicate inside. We have recently used electron microscopy to examine these infectious bacteria in great detail. We have been able to see the bacteria in the process of entering cells when their molecular syringe first contacts the host surface and see in much more detail how the bacteria enter into our cells. Many scientists have studied the syringes by isolating them, but in the process important parts are lost. Our proposed experiments will examine the structure of the intact syringe while it is in the bacterial membrane and when it contacts the host cell. The findings will not only provide important new information about how Chlamydia cause disease, which might eventually lead to new treatments, but also other disease-causing bacteria that have very similar syringes.