Manipulation Of Host Signal Transduction Pathways And Cytoskeleton Functions By Invasive Bacterium Listeria Monocytogenes And Chlamydia Trachomatis

Publication Year:
2012
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Repository URL:
http://stars.library.ucf.edu/etd/2334
Author(s):
Jiwani, Shahanawaz
Tags:
Actin; listeria; chlamydia
thesis / dissertation description
Infectious disease remains one of the leading causes of morbidity and mortality worldwide. Many bacteria that cause disease have the capacity to enter into eukaryotic cells such as epithelial cells and tissue macrophages. Gaining access into the intracellular environment is one of the most critical steps in their survival and/or in pathogenesis. The entry mechanisms employed by these organisms vary considerably, but most mechanisms involve sabotaging and manipulating host cell functions. Invasion of epithelial cells involves triggering host signal transduction mechanisms to induce cytoskeleton rearrangement, thereby facilitating bacterial uptake. My work focuses on understanding the molecular mechanisms employed by bacterial pathogen Listeria monocytogenes and Chlamydia trachomatis to gain access into the host cells in order to cause the disease. In first part of my thesis I investigated the mechanism of Listeria monocytogenes entry. Listeria, a facultative intracellular organism, is responsible for causing meningitis, septicemia, gastroenteritis and abortions. Critical for Listeria virulence is its ability to get internalized, replicates and spread into adjacent host cells. One of the pathways of Listeria internalization into mammalian cells is promoted by binding of its surface protein Internalin B (InlB) to host receptor MET. Studies done in the past demonstrated a critical role of host type IA Phosphoinositide (PI) 3-kinase in controlling cytoskeleton rearrangement and entry of Listeria downstream of MET. An important unresolved question was how activation of PI3K results in cytoskeleton rearrangements that promote Listeria entry. In this work, we identified 9 host signaling molecules, that iv includes Rab 5c, SWAP 70, GIT1, PDK1, mTor, ARAP2, ARNO, DAPP1 & PKC-δ, acting downstream of type IA Phosphoinositide (PI) 3-kinase to regulate changes in host cytoskeleton to cause Listeria entry. Second part of my thesis involved studying the functions of chlamydial effector protein Tarp in its invasion. Infection caused by Chlamydia Trachomatis is the most common sexually transmitted disease resulting in uro-genital diseases, LGV, ectopic pregnancy and infertility. It is also responsible for causing trachoma, the leading cause of preventable blindness in third world countries. Being an obligate intracellular pathogen, gaining access into intracellular environment is the most critical step in lifecycle and pathogenesis of Chlamydia. Previous studies demonstrate the role of both chlamydial and host actin nucleators, Tarp and Arp2/3 complex respectively, in mediating Chlamydial entry into non-phagocytic cells. But the molecular details of these processes were not well understood. In this study, we demonstrate novel function of Tarp protein to form actin bundles by its ability to bind filamentous actin through newly identified FAB domains. And we also provide bio-chemical evidence that Tarp and Arp2/3 complex works in conjunction to cause changes in host cytoskeleton that effectively culminate into bacterial uptake by host cells. Overall, this research was a significant step in enhancing our understanding, at a molecular level, to pathogenesis of infections caused by Listeria monocytogenes and Chlamydia trachomatis