50-70% of Chlamydia trachomatis infections, the most common cause of bacterial sexually transmitted infections, are asymptomatic. This increases the risk of widespread transmission and untreated infections, resulting in pelvic inflammatory disease or infertility in women. Further, the CDC estimates that 10% of women between the ages of 15 to 19 test positive for Chlamydia. Hence, there is a great need to identify strategies to reduce/prevent transmission, limit infections to the primary site of inoculation or interrupt/control chlamydial growth and development. Within the host cell, elementary bodies (EBs) differentiate into reticulate bodies (RBs) in a pathogen-specified parasitic organelle termed the chlamydial inclusion. To maintain its autonomy, the chlamydial inclusion interacts with very specific host cell pathways, which ultimately influences the lipid an protein content of the inclusion. Paramount to chlamydial survival within the host is the organism's ability to obtain and utilize host cell-derived lipids. These lipids contribute to the membrane of the chlamydial inclusion, as well as, the chlamydial cell membranes. It is well established that Chlamydia will mimic the lipid composition of their host cells, but the organisms will not incorporate all available host-derived lipids into their cell membranes. During development, the RB has a close association with the inner leaflet of the chlamydial inclusion, where it acquires lipids. This is consistent with the notion that the specificity of interaction ofthe chlamydial inclusion membrane with host cell vesicles is not only important for the maintenance of the pathogen-specific parasitic organelle, but ultimately, is important for dictating the lipid content of the pathogens. Our laboratory focuses on the function of eukaryotic SNAREs at the chlamydial inclusion. SNARE proteins serve to decrease the energy required to fuse a host vesicle with a target membrane. In this case, the target membrane is the chlamydial inclusion. We have demonstrated that syntaxins 6 and 10 and VAMPs 3 and 4 localize to chlamydial inclusion. Further, we have demonstrated that syntaxin 6 and VAMP4 (2 out of 4 required proteins to form a fusogenic SNARE complex) interact at the chlamydial inclusion. We hypothesize that the chlamydial inclusion specifically intercepts multiple fusogenic SNARE complexes to create and maintain a defined lipid composition in the inclusion membrane. To test this hypothesis, first, we will identify the eukaryotic and chlamydial binding partners for SNARE proteins known to localize to the inclusion, as protein-protein interactions often dictate purpose. Second, we will knockdown these proteins to understand the role of these proteins in determining chlamydial lipid content and subsequent outer membrane organization. Third, we will determine how knockdown of these proteins affects chlamydial growth and development. By examining protein-protein interactions that occur at the chlamydial inclusion, we will determine how SNARE proteins contribute to chlamydial lipid content, and ultimately, to chlamydial pathogenesis. These studies will underlay the bases for strategies to alter chlamydial infectivity via interruption of lipid acquisition to the inclusion membrane, which will ultimately impact the infection and transmission rates of Chlamydia.
Current strategies to prevent and limit chlamydial infection are ineffective, resulting in $700 million medical costs. A strategy that Chlamydia uses to survive in the host is the acquisition host derived lipids. Studies in this application seek to understand chlamydial mechanisms of lipid acquisition and the role these lipids play in chlamydial pathogenesis.
| Rucks, Elizabeth A; Olson, Macy G; Jorgenson, Lisa M et al. (2017) Development of a Proximity Labeling System to Map theChlamydia trachomatisInclusion Membrane. Front Cell Infect Microbiol 7:40 |
| Fozo, E M; Rucks, E A (2016) The Making and Taking of Lipids: The Role of Bacterial Lipid Synthesis and the Harnessing of Host Lipids in Bacterial Pathogenesis. Adv Microb Physiol 69:51-155 |
