Deciphering the role of the host endoplasmic reticulum in Chlamydia inclusion biogenesis

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Many 'friendly' bacteria live passively in the environment or engage in mutually 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 detect how these syringes and effectors operate. Remarkably, the results so far are not only beginning to tell us how many bacteria cause disease, but they are also providing astonishing new insights into how our own cells function, as the bacteria have been perfecting their armaments for millions of years. Paradoxically, these bacterial effectors therefore also provide exquisite and exciting new tools to study cell biology.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 difficult to study Chlamydia in the laboratory as they cannot grow outside host cells at all and unlike other bacteria they cannot yet be genetically manipulated. Chlamydia use a molecular syringe to deliver effectors that enable the bacteria to replicate inside a special membrane-bound compartment inside host cells called the 'inclusion'. We have recently shown that the inclusion interacts with an important host membrane system called the endoplasmic reticulum (ER), which manufactures host proteins. We showed that this novel interaction is critical to bacterial survival and infectivity. In fact, the ER contacts the inclusion at the points where the bacteria assemble their syringes, structures we call 'pathogen synapses'. Our proposed experiments will examine why this interaction with the ER is so important and how it might relate to the delivery of effectors through the syringe. The findings will not only provide important new information about how Chlamydia cause disease, which might eventually lead to new treatments, it might also illuminate the fundamental pathways cells use to control their intracellular compartments and the synthesis of their own proteins.