| Description |
Urinary tract infections (UTI) are one of the most prevalent human diseases, with uropathogenic Escherichia coli (UPEC) being the primary cause of Gram-negative UTIs. Left untreated, bacteria can ascend from the bladder to the kidneys and eventually escape into the blood stream, causing a potentially lethal case of sepsis. With the shocking increase of antibiotic resistance, new treatments are necessary to combat these infections. UPEC are invasive bacteria that reside within host cells and can remain in a quiescent, metabolically inactive state that renders most current generation antibiotics useless. The primary aims of this dissertation are: 1. to identify host factors important for bacterial invasion and 2. determine how sensing of the bacteria by the innate immune system contributes to persistence or clearance of uropathogens. First, I investigated how plant-based natural products could be used to prevent UPEC invasion into host bladders. These natural products are often used as a part of traditional medicinal practices and may hold promising new methods of treatment for UTIs. The natural products tested successfully inhibited invasion into host cells in an in vitro model of UTI through inhibition of the focal adhesion kinase host factor. When tested in an in vivo model of UTI, invasion into bladder cells was also inhibited. Next, I investigate the role of the host protein histone deacetylase 6 (HDAC6) in an in vitro and in vivo model of UTI in both the somatic and hematopoietic compartments. I discovered that although HDAC6 is a vital factor for host cell invasion in an in vitro model, in an in vivo HDAC6 knockout model bacteria were better able to invade the bladder mucosa at an early time point. Although there are elevated titers in HDAC6 knockouts very early, it is rapidly brought under control and remains near wild type levels through the examined time points. Investigation of neutrophils revealed both genotypes recruit similar numbers, though HDAC6 knockout neutrophils contain higher numbers of viable bacteria. Finally, I investigated the interplay between a bacterial motility organelle and its corresponding receptor in the host, Toll-Like Receptor 5, to elaborate how pro-inflammatory signaling through the receptor altered the host's ability to resolve a UTI. Overall, the sum of the research presented in this dissertation aims to identify the host factors important for bacterial invasion and persistence with the goal to eventually develop ways to manipulate the host to better treat UTIs and prevent recurrent UTIs. |
