Date on Master's Thesis/Doctoral Dissertation
Microbiology and Immunology
Microbiology and Immunology, PhD
Committee Co-Chair (if applicable)
bacterial pathogenesis; plague; zinc; nutritional immunity; calprotectin
Yersinia pestis is a Gram-negative re-emerging bacterial pathogen that is responsible for bubonic, septicemic, and pneumonic plague. Y. pestis and other bacteria require transition metals, such as iron, zinc, and manganese, to maintain intermediary metabolism, transcriptional regulation, and virulence. To inhibit infection, eukaryotic organisms have developed distinct mechanisms, called nutritional immunity, to sequester these important nutrients from invading bacteria. For pathogens to colonize the vertebrate host, they have evolved dedicated acquisition systems for transition metals. During infection, Y. pestis overcomes iron limitation by secreting the siderophore yersiniabactin. Additionally, Y. pestis requires zinc for infection and utilizes high affinity transporters to overcome zinc restriction. The first zinc importer identified in Y. pestis was the ZnuABC transport system, which is essential for in vitro growth. Notably, ZnuABC is not required for Y. pestis virulence. Thus, while zinc acquisition is recognized as important for bacterial pathogenesis, there is a gap in our understanding of zinc uptake by Y. pestis. Recently, an unexpected role for the yersiniabactin system was identified for growth in zinc limited medium. Moreover, a znuBC mutant that lacks genes involved in yersiniabactin synthesis (e.g., irp2) was completely attenuated for virulence. These data suggested yersiniabactin might be involved in zinc acquisition during infection. The findings I present here are the first to demonstrate a novel role for yersiniabactin in zinc acquisition in Y. pestis. I also show that this conceptually novel mechanism allows Y. pestis to overcome zinc nutritional immunity in both the mammalian and insect host. Furthermore, using a technically innovative approach called droplet Tn-seq, I was able to identify the primary secretion mechanism for yersiniabactin. These studies not only provide a significantly better understanding of the role for yersiniabactin-dependent zinc acquisition in Y. pestis virulence, but since yersiniabactin is a conserved virulence factor in other Gram-negative pathogens, also provide new insight into how a variety of other pathogens acquire zinc during infection. Furthermore, since yersiniabactin is essential for virulence, my identification of the yersiniabactin secretion system represents a novel target for the development of an anti-virulence therapeutic that could be used to combat infections by multiple bacteria.
Price, Sarah, "Identification of a role beyond iron acquisition for yersiniabactin during Yersinia pestis infection." (2023). Electronic Theses and Dissertations. Paper 4087.