ORCID

0000-0002-2312-2305

Date of Award

2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cellular, Molecular and Biomedical Sciences

First Advisor

Matthew J. Wargo

Abstract

Sphingolipids are critical to eukaryotic cell membrane structure and function and play important bioactive roles in regulating processes such as cell growth and differentiation, apoptosis, phagocytosis, and pathogen defense. Specifically related to bacterial infections, sphingoid bases such as sphingosine are potent antimicrobial lipids with activity against a variety of Gram-negative and Gram-positive bacteria. Additionally, bioactive sphingolipids, such as ceramide and sphingosine-1-phosphate, regulate phagocytic cell function and help elicit inflammatory responses.

Given the importance of sphingolipids to the host, it is not surprising that many pathogens evolve the capability to alter host sphingolipid homeostasis, promoting pathogenesis. Pseudomonas aeruginosa is a common opportunistic pathogen especially in the health care setting. P. aeruginosa is less susceptible to sphingosine’s antimicrobial activity than many Gram-negative bacteria. Previous data from our lab showed that exposure of P. aeruginosa to sphingosine or sphingosine-rich host environments leads to induction of a small set of sphingosine-responsive genes in an SphR-dependent manner. These genes protect P. aeruginosa from growth inhibition by sphingosine while also promoting pathogenesis strategies.

My dissertation focused on identifying the metabolic function of the sphingosine-responsive gene products and understanding the impact they have on the host. We determined that the sphingosine-induced metabolic operon, sphBCD, is important for P. aeruginosa growth in the presence of sphingosine through sphingosine detoxification. Additionally, we demonstrated that PlcH, a known virulence factor and sphingosine-induced sphingomyelinase, can hydrolyze sphingosylphosphorylcholine (SPC), an important host bioactive sphingolipid responsible for regulating critical cellular and tissue responses. Lastly, we investigated the impact the sphingosine-responsive genes have on the host. Here, cerN, encoding a ceramidase, seems to play a role in P. aeruginosa evasion of macrophage phagocytosis, decreasing overall phagocytic engulfment. Our data underscore the interplay between P. aeruginosa and host sphingolipid axis exploitation, demonstrating mechanisms by which P. aeruginosa can both bypass host antimicrobial tactics and degrade critical host bioactive molecules.

Language

en

Number of Pages

310 p.

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