Dissertation
Brucella Modulation Of Host Secretory Membrane Compartments Via Multiple Type IV Effector Proteins
Washington State University
Doctor of Philosophy (PhD), Washington State University
2023
DOI:
https://doi.org/10.7273/000005004
Abstract
Intracellular bacterial pathogens cause many infectious diseases of public health importance, where they modulate cellular functions during their lifecycle to promote essential virulence traits such as proliferation, dissemination, or persistence. Despite their significance, the underlying mechanisms of these virulence strategies are rarely understood, which limits our knowledge of bacterial pathogenesis. Species of the genus Brucella are highly infectious bacteria that cause the worldwide zoonotic disease, brucellosis, and their proliferation within phagocytes depends on the expression of a Type IV Secretion System (T4SS) that delivers effector proteins into the host cell and mediates biogenesis of the replicative Brucella-containing vacuole (rBCV). Determining the functions of these individual T4SS effector proteins is central to our understanding of how Brucella generates its intracellular niche to establish a successful infection. Several T4SS effector proteins have been identified, however their functions and role during Brucella infection remains largely unknown. Here, we describe the function of four T4SS effector proteins, BspB, RicA, BspA and BspF, and how they contribute to rBCV biogenesis or intravacuolar replication of the bacterium by targeting secretory compartments. BspB and RicA engage Rab2 functions in an antagonistic manner to balance endoplasmic reticulum (ER)-to-Golgi apparatus vesicular transport to support rBCV biogenesis. BspA promotes bacterial replication in rBCVs by inhibiting ER associated degradation (ERAD) through interactions with the E3 ubiquitin ligase, MARCH6, thereby interfering with E3 ubiquitin complex function. BspF interacts with the Arf6 GTPase activating protein (GAP) ACAP1, resulting in blockage of Arf6/Rab8a-dependent retrograde transport at the recycling endosome (RE) to promote intravacuolar replication. BspF contains a Gcn5-related N-acetyltransferase domain which is important for its interaction with ACAP1 and inhibition of retrograde transport. This work provides some of the first functional insight into how multiple T4SS effector proteins target distinct secretory membrane compartments to contribute to Brucella’s infectious cycle.
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Details
- Title
- Brucella Modulation Of Host Secretory Membrane Compartments Via Multiple Type IV Effector Proteins
- Creators
- Elizabeth Maeve Borghesan
- Contributors
- Jean Celli (Advisor)Thomas Kawula (Committee Member)Dana Shaw (Committee Member)Anders Omsland (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- College of Veterinary Medicine
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 241
- Identifiers
- 99901019835001842
- Language
- English
- Resource Type
- Dissertation