Regulation and composition of ER-inclusion contacts at key stages of the Chlamydia developmental cycle

点击翻译按钮获取中文摘要

SUMMARY Chlamydia trachomatis is the leading cause of sexually transmitted infections of bacterial origin worldwide. Vaccines are not available. Infections are often asymptomatic and left untreated, resulting in tissue scarring and long-term consequences on female reproductive health. C. trachomatis is an obligate intracellular bacterial path- ogen that undergoes a bi-phasic development cycle within a membrane bound compartment termed the inclu- sion. To thrive in this confined environment, C. trachomatis must interact with cytosolic host factors and orga- nelles, a process mediated by the insertion of Chlamydia specific Inclusion membrane proteins (Inc proteins) into the inclusion membrane. One such interaction is the intimate contact between discrete sections of the inclu- sion membrane and the endoplasmic reticulum (ER). These structures are referred to as ER-Inclusion membrane contact sites (MCS). Our initial characterization of ER-Inclusion MCS indicates an enrichment in Inc proteins and host factors with functional, tethering and regulatory capacities. Depletion of some of these components is detrimental to bacterial growth, underscoring the important role of ER-Inclusion MCS in establishing the replicative niche. ER-Inclusion MCS are observed throughout the developmental cycle; however, it remains unclear if and how functional, structural and regularoty components cooperate in the temporal assembly and dissambly of the contact, and enrichment of specific components. Here we will investigate how ER-Inclusion MCS assembly is regulated (Aim 1) and if association of specific components varies depending on the stage of the developmental cycle (Aim 2). Altogether, the proposed studies will elucidate how components of ER-Inclusion MCS allows for the establishment of the C. trachomatis replicative niche, which will guide the design of effective therapeutics.