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Date of Award
Doctor of Philosophy (PhD)
Bacteria rarely live in isolation. Instead, they live within dense communities that are shaped and maintained by cooperative and antagonistic interactions between diverse bacterial species. Interbacterial interactions occur in essentially any environment bacteria inhabit, including the human host. Thus, the consequences of these interactions are extensive, impacting human health and disease, agriculture, and bacterial evolution. Interbacterial antagonism is of particular interest because it plays a direct role in nutrient acquisition and niche establishment. Elucidation of the mechanisms and molecules underlying interbacterial antagonism may reveal novel strategies to combat infections by multidrug resistant pathogens.
Antagonism between Gram-negative bacteria is largely mediated by the contact-dependent delivery of toxic effector proteins via the type VI secretion system (T6SS). This dynamic nanoweapon is composed of an effector-loaded spiked tube complex that is encompassed by a contractile sheath. When the sheath contracts, it propels the spiked tube and associated effectors from the attacking cell to adjacent bacterial competitors, leading to contact-dependent bacterial killing. Effector-encoding bacteria prevent self-intoxication and kin cell killing by the expression of immunity proteins, which neutralize effector toxicity by specifically binding their cognate effector and occluding its active site. Much of the research on the T6SS has focused on classical model organisms, such as Escherichia coli, Pseudomonas aeruginosa, and Vibrio cholerae, and it has uncovered a remarkable level of information regarding the molecular details of this machine and its role in bacterial ecology and virulence. However, the T6SS of other bacteria remain poorly characterized.
The work described herein provides novel insights into the regulation, architecture, and function of the T6SS of the human pathogen Acinetobacter baumannii. First, we identify a unique architectural requirement of the T6SS of A. baumannii. Additionally, we employ murine pneumonia and catheter-associated urinary tract infection models to study the role of the T6SS in A. baumannii virulence. Finally, we establish a novel family of formylglycine-generating enzyme (FGE)-like T6SS immunity proteins that are widespread among Gram-negative bacteria. The findings from this work open new avenues for research into Acinetobacter biology, and they expand our understanding of the molecular intricacies underlying antibacterial nanoweapons.
Chair and Committee
Mario F. Feldman
Juliane Bubeck Wardenburg, Michael G. Caparon, Scott J. Hultgren, Joseph M. Jez,
Lopez, Juvenal, "Regulation, Architecture, and Function of the Type VI Secretion System of Acinetobacter baumannii" (2021). Arts & Sciences Electronic Theses and Dissertations. 2510.
Available for download on Tuesday, August 17, 2100