Dissertation
Manipulation of Golgi-associated functions by Type IV effectors supports Brucella intracellular cycle
Doctor of Philosophy (PhD), Washington State University
01/2019
Handle:
https://hdl.handle.net/2376/117918
Abstract
Intracellular bacterial pathogens have developed various strategies to survive and proliferate within host cells. Common to most intracellular bacteria are specialized secretion systems that deliver effectors to hijack host cell functions to support bacterial replication, inhibit immune detection, and promote successful dissemination. The bacterium Brucella spp. is the causative agent of the world-widespread zoonotic disease brucellosis. The ability of Brucella to establish a successful infection is dependent on the VirB Type IV secretion system (T4SS), and we herein describe an additional requirement of this secretion system for bacterial egress from the host cell. Essential to understanding the mechanisms used by Brucella to create its intracellular niche is the characterization of T4SS-delivered effectors. A number of Brucella effectors have been identified, yet the mechanisms by which they act on the host cell and how they promote pathogenesis remain mostly unknown. Here we have described functions of three Brucella VirB T4SS effectors, BspB, RicA, and BspF, which target host secretory vesicular traffic to promote biogenesis of the replicative Brucella-containing vacuole (rBCV) and support bacterial proliferation. Using molecular and cellular approaches, we have uncovered the importance of BspB in rBCV biogenesis and of BspF in bacterial replication. Upon translocation into the host cell, BspB interacts with the conserved oligomeric Golgi (COG) tethering complex to redirect Golgi-derived vesicles to the BCV, a process that contributes to rBCV biogenesis. The interaction between BspB and the secretory pathway results in disruption of anterograde ER-to-Golgi transport, however the Rab2-interacting effector RicA inhibits retrograde Golgi-to-ER vesicular traffic. Together these two effectors alter antagonistic host functions to balance ER-Golgi secretory trafficking during infection. In addition to inhibiting secretory transport, the effector BspF binds to ACAP1 and Optineurin, two regulators of host vesicular traffic, and modulates vesicle transport through the recycling endosome. These findings provide among the first mechanistic insights into Brucella effector functions and characterize distinct secretory and recycling trafficking pathways that contribute to the infectious cycle of Brucella.
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Details
- Title
- Manipulation of Golgi-associated functions by Type IV effectors supports Brucella intracellular cycle
- Creators
- Erin Patterson Smith
- Contributors
- Jean Celli (Advisor)Michael E Konkel (Committee Member)Anthony V Nicola (Committee Member)Alan G Goodman (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- School of Molecular Biosciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 237
- Identifiers
- 99900581504501842
- Language
- English
- Resource Type
- Dissertation