Author

Xi ChenFollow

Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

Abstract

The Gram-positive bacterium Staphylococcus aureus is a major threat to public health and causes a multitude of infections, ranging from mild skin and soft infection, to more severe diseases including sepsis, osteomyelitis and infective endocarditis. As a successful pathogen, S. aureus employs various mechanisms to invade host tissues, evade immune responses, and survive in the host environment. One critical adaptive trait of S. aureus that promotes virulence and survival is the ability to maintain membrane homeostasis via flexible modifications to its lipid composition in response to the surrounding lipid environment. Phospholipids are the major component of the bacterial membrane and the composition of their fatty acyl chains serve as the primary determinants of membrane fluidity and bacterial viability. Furthermore, phospholipids serve as intermediates in lipoprotein synthesis by providing a source of acyl chain moieties that comprise the lipoprotein membrane anchor. Lipoproteins are important for nutrient acquisition and their acyl chain moieties are critical pathogen associated molecular patterns that activate Toll-like receptor 2 (TLR2)-mediated innate immune responses. S. aureus employs de novo fatty acid synthesis and environmental acquisition mechanisms to control the composition and adjust the structure of the acyl chains that are present in the membrane. Over the past 20 years, a number of studies have identified the enzymes that are responsible for these processes. However, the ramifications of lipid composition variability on S. aureus virulence and immune responses are comparatively understudied. In this thesis, we uncovered novel roles for secreted lipases and lipid homeostasis in S. aureus pathogenesis. First, we determined that the S. aureus secreted lipase, Geh, inactivates bacterial lipoproteins, the critical ligands of TLR2, to blunt innate immune responses and facilitate persistence during infection. Second, we found that the homeostasis between host unsaturated fatty acid incorporation and de novo branched chain fatty acid synthesis contributes to S. aureus immune evasion during infection. A branched chain fatty acid auxotroph requires incorporation of host derived unsaturated fatty acids for survival, but at a cost of heightened TLR2-induced immune activation. Intriguingly, this phenomenon is prevented on account of de novo synthesis of branched chain fatty acids. We found that lipoproteins with branched chain fatty acid moieties are a more likely target for Geh-mediated inactivation, while attachment of unsaturated fatty acids yields lipoproteins that are potent TLR2 agonists and poorer substrates for Geh. Altogether the data in this thesis provides new insight into the critical roles of lipids and lipid homeostasis in promoting the optimal environment for bacterial survival during infection.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

Available for download on Saturday, October 07, 2023

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