Author ORCID Identifier

https://orcid.org/0009-0000-3858-0010

Date of Award

5-6-2024

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

First Advisor

Dr. Cynthia Nau Cornelissen

Second Advisor

Dr. Timothy Luke Denning

Third Advisor

Dr. Zehava Eichenbaum

Abstract

Gonorrhea is a sexually transmitted infection, caused by the bacterial pathogen Neisseria gonorrhea (Ngo) and affects millions of individuals of all age groups across the globe every year. Infection with Ngo does not result in protection and no effective vaccine has been developed, leaving antibiotics as the only treatment option. With the emergence of strains showing high levels of antibiotic resistance, there is an urgent need for development of novel therapeutics for disease prevention. During pathogenesis the host employs nutritional immunity, to restrict important transition metals such as zinc away from Ngo. This process is counteracted in Ngo by the production of highly efficient zinc import TonB-dependent Transporters (TDTs) which are promising vaccine antigens and zinc shuttle ABC transporters found to be important for intracellular survival. In Ngo zinc homeostasis and transport proteins are regulated by the Zinc uptake regulator (Zur) which represses transcription in the presence of zinc and activates transcription in the absence of zinc. In this study, we performed RNA sequencing to identify the global profile of genes in Ngo under the control of Zur and found that it differentially regulates 26 genes in response to zinc levels. We report the activity of Zur activity as a global regulator, able to both repress and activate gene expression in the presence of zinc and identified a consensus region on their promoters. We went on to further characterize the promoter elements of the zinc import TDT, tdfJ, which results in dual regulation by zinc and iron. We characterize specificity and binding affinities for regulation of tdfJ by a second regulator, Ferric uptake regulator (Fur) in response to iron. The response of tdfJ to both iron and zinc and its potential to be an important invasin, makes it an attractive candidate to investigate female genital tract infections. The female genital tract is a conglomerate of these conditions and infections here are often asymptomatic. Taken together, this research provides important knowledge on the regulation of virulence mechanisms in response to zinc, which will aid in the development of therapeutics and an efficacious vaccine against a gonococcal infection.

DOI

https://doi.org/10.57709/36902798

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