Chlamydia trachomatis is a gram-negative bacterial pathogen of tremendous public health concern. Ocular serovars lead to trachoma and genital serovars are the leading cause of bacterial sexually transmitted disease in developed countries. Despite the implementation of C. trachomatis screening programs and the effectiveness of a single-dose of azithromycin to treat trachoma and uncomplicated sexually transmitted chlamydial infection, case rates are not declining and reinfection rates are increasing. If our knowledge of the cellular processes targeted by C. trachomatis has greatly increased over the past 10 years, we have only begun to identify the host and bacterial factors required for bacterial development. This paucity of knowledge is due to the fact that Chlamydia are obligate intracellular pathogens with limited genetic tools available. We have contributed to the field through the identification of host factors required for Chlamydia infection using the RNAi methodology. Moreover, in the light of the recently described C. trachomatis transformation method, we have developed a versatile cloning vector for gene expression in C. trachomatis. Our genetic investigations led to the identification of CERT, a protein involved in the non-vesicular trafficking of ceramide, as a factor required for C. trachomatis growth. We further showed that CERT recruitment to the inclusion correlated with the recruitment of ER tubules in close proximity of the inclusion membrane. Moreover, we identified the C. trachomatis inclusion membrane protein IncD as a specific binding partner for CERT. Altogether, these results led us to propose the notion that C. trachomatis establishes direct membrane contact sites with the ER and exploits non-vesicular transport machinery The goal of this new R01 application is to further characterize the structure and function of ER-Inclusion MCSs during C. trachomatis infection. Our hypothesis is that specific C. trachomatis and host factors localize to ER-Inclusion MCSs and create a specialized microenvironment that mediate the bacterial acquisition of essential nutrients, such as lipids. To test our hypothesis, we propose to determine whether sphingomyelin synthesis occurs at ER- Inclusion MCSs (Aim1), to characterize the C. trachomatis components of ER-Inclusion MCSs (Aim2) and to characterize the cellular components of ER-Inclusion MCSs (Aim3). At the conclusion of Aim1, 2 and 3, we will have gained a considerable amount of information on the formation and function of ER-Inclusion MCSs. We believe that these ER-Inclusion MCSs play an important role during C. trachomatis developmental cycle through the efficient acquisition of nutrients such as lipids. Our approach will identify both bacterial and host factors that localize to these MCSs and therefore help us better understand the function of ER-Inclusion MCSs at the molecular level. This will further our understanding of the molecular mechanisms involved in the infection process and may reveal drug targets to facilitate the translational research development of tools to prevent, treat and control Chlamydia infection.

Public Health Relevance

Chlamydia trachomatis are obligate intracellular bacterial pathogens responsible for trachoma and sexually transmitted diseases. We study how Chlamydia hijack cellular components to successfully replicate and disseminate inside the host. We focus on dissecting the cellular mechanism(s) involved in the infection process by identifying the Chlamydia and host factors required for Chlamydia development. The identification of these factors may help design new therapeutic treatments.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Host Interactions with Bacterial Pathogens Study Section (HIBP)
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Hiltke, Thomas J
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Yale University
Schools of Medicine
New Haven
United States
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Stanhope, Rebecca; Derré, Isabelle (2018) Making Contact: VAP Targeting by Intracellular Pathogens. Contact (Thousand Oaks) 1:
Han, Ying; Derré, Isabelle (2017) A Co-infection Model System and the Use of Chimeric Proteins to StudyChlamydiaInclusion Proteins Interaction. Front Cell Infect Microbiol 7:79
Stanhope, Rebecca; Flora, Elizabeth; Bayne, Charlie et al. (2017) IncV, a FFAT motif-containing Chlamydia protein, tethers the endoplasmic reticulum to the pathogen-containing vacuole. Proc Natl Acad Sci U S A 114:12039-12044
Derré, Isabelle (2016) Basic Research in Bacterial Pathogenesis: ""What's Your Job about, Exactly?"" PLoS Pathog 12:e1005612
Derré, Isabelle (2015) Chlamydiae interaction with the endoplasmic reticulum: contact, function and consequences. Cell Microbiol 17:959-66
Agaisse, Hervé; Derré, Isabelle (2015) STIM1 Is a Novel Component of ER-Chlamydia trachomatis Inclusion Membrane Contact Sites. PLoS One 10:e0125671
Mirrashidi, Kathleen M; Elwell, Cherilyn A; Verschueren, Erik et al. (2015) Global Mapping of the Inc-Human Interactome Reveals that Retromer Restricts Chlamydia Infection. Cell Host Microbe 18:109-21