Chlamydia trachomatis is the leading cause of bacterial sexually transmitted infections
worldwide and it has been linked to increased risks of cervical cancer. Our study aims to understand the mechanisms by which chlamydia infection contributes to higher risks of tumorigenesis. We discovered in over 90% of infected human epithelial cells that chlamydia inclusions localized to the host cell centre during mitosis and prevented the completion of cleavage furrow ingression. Infected cells that failed to divide into two daughter cells re-entered
interphase as tetraploid multinuclear cells, which are known initiators of tumorigenesis. In order to address whether chlamydia actively sought the host cell centre during mitosis, we created vacuoles using internalized latex beads and our findings indicated that chlamydia inclusions
localized to the host cell centre much more frequently than similarly sized vacuoles. In addition, we demonstrated that metabolically inactive chlamydia inclusions localized to the cell centre less frequently than inclusions under normal conditions. Together, these results suggested that
chlamydia actively localized to the host cell centre to efficiently block host cell mitosis. We took advantage of the microtubule-displacing capability of the C. trachomatis inclusions and demonstrated that astral microtubules could promote furrow initiation independent of the central spindle microtubules. Microdomains on chlamydia inclusions play important roles in inclusion localization and chlamydia replication. We discovered that these structures were surprisingly resistant to
bacterial protein synthesis and host Src family kinase inhibitors. Finally, we demonstrated that multinuclear cells that resulted from unsuccessful mitosis contained significantly higher Golgi content, an important nutrient source for chlamydia. Our results indicated that C. trachomatis in
multinuclear cells intercepted Golgi-derived lipids faster than in mononuclear cells. Together, my results reveal that C. trachomatis inclusions robustly localize to the cell centre to block host cell mitosis in order to acquire host Golgi nutrients more quickly in multinucleated cells.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/65754 |
| Date | 01 September 2014 |
| Creators | Sun, He Song |
| Contributors | Rene, Harrison |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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