Defining stress resistance and persistence properties of uropathogenic E. Coli

Uropathogenic Escherichia coli (UPEC) cause the overwhelming majority of community-acquired urinary tract infections (UTI) worldwide. A particularly problematic aspect of UPEC-associated UTI is the rate of recurrent infections- one in four UTIs will recur within six months of the initial infection. In the majority of cases, the strain responsible for the primary infection is identical to the strain causing the recurrent infection. Usually, the urinary tract is maintained as a sterile environment by an array of host defenses. Some of the genetic mechanisms by which UPEC cope with or subvert host defenses in order to colonize and persist within the urinary tract is the primary focus of this thesis. I start by exploring the effects of global metabolic and stress response transcriptional regulation on the virulence potential of UPEC within the murine urinary tract. Therein, I better define the metabolic and stress response limitations affecting UPEC colonization of this niche. I then address the advantages of chromosomally encoded toxin-antitoxin systems in allowing for niche-specific colonization of the urinary tract and explore how these small genetic elements can specifically affect the stress resistance and antibiotic persistence of UPEC. This work, specifically, identifies a novel target for chemotherapeutic agents that would theoretically home in on and hinder only uropathogenic subsets of E. coli, combating UTI while leaving commensal E. coli iv unphazed. Lastly, I attempt to better understand the generation of UPEC stress resistance by studying the evolutionarily conserved genomic rearrangement of chromosomally encoded toxin-antitoxin hicAB within these pathogens. I found that constructing this evolutionarily conserved hicAB truncation within the ancestral E. coli MG1655 promotes serum resistance and survival of this characteristically nonpathogenic strain of E. coli within the blood of a murine host. Furthermore, ancestral strains carrying this truncated allele are, in general, more resistant to stress than their unevolved counterparts. In total, this body of work better defines the stress resistance and persistence capacities of UPEC.