Novel approaches to identify host genes required for Chlamydia pathogenesis

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DESCRIPTION (provided by applicant): Chlamydia trachomatis and C. pneumoniae are important causes of human infections and disease. C. trachomatis , is the major cause of non-congenital blindness in the third world and a leading cause of sexually transmitted diseases and non-congenital infertility in Western countries. C. pneumoniae causes a wide range of respiratory infections. The extraordinary prevalence and array of these diseases as well as their capacity to lead to infertility, blindness, and various chronic states make them public concerns of the first importance. Although infections can be treated with antibiotics, no drug is cost-effectiv enough for widespread elimination of the disease in underdeveloped countries, and attempts at vaccines have been unsuccessful. A detailed understanding of the life cycle and the mechanisms of pathogenesis have been hindered by the lack of Chlamydia genetics, but we have now made substantial inroads into understanding Chlamydia pathogenesis by monitoring its effects on the cell biology of the host. These studies are essential to identify new strategies for treatment and prevention. All Chlamydia species are obligate intracellular parasites that must establish a privileged niche (a membrane bound compartment termed the inclusion) in order to survive and replicate in the hostile intracellular environment. Recent transformative research from our lab and others reveals that the inclusion is not an isolated compartment devoid of interactions with the host. Instead, we now understand that Chlamydia, despite its small genome size, encodes well over 100 proteins that are secreted that function to selectively recruit organelles and to manipulate host cell trafficking pathways, allowing Chlamydia to acquire essential nutrients and escape detection by the host immune response. Indeed, subversion of host cell trafficking pathways is emerging as a common theme in successful intracellular microbes. Further unraveling these complex events will yield important clues into the pathogenesis of infectious disease as well as provide novel insights into fundamental eukaryotic cell biology, with implications ranging from developmental biology to cancer biology. Our short term goals are as follows: Aim 1. We will investigate how C. trachomatis utilizes Arf1 to establish a unique intracellular niche. Aim 2. We will investigate the hypothesis that Chlamydia establishes an "onsite" lipid biosynthetic factory at the inclusion membrane that is necessary for bacterial replication and inclusion growth and stability. Aim 3. We will use state of the art biochemical and imaging techniques to gain a mechanistic understand of chlamydial inclusion fusion. Together, these findings will increase our basic knowledge of the pathogenesis of intracellular infections. In addition, they have the potential to identify new targets for the development of new therapeutic, diagnostic, and preventative therapies.