Date of Award
Doctor of Philosophy (PhD)
Urinary tract infections (UTIs) are the second most common bacterial infection of people in the U.S.A and are frequently recurrent, as an initial UTI is quickly followed by a second episode in 30-35% of cases despite appropriate antibiotic treatment and clearance of the bacteria from the urine. The vast majority, >80%, of UTIs are caused by uropathogenic Escherichia coli (UPEC). UPEC that colonize the bladder are thought to originate in the gut, where they live as commensal organisms. UPEC can be shed in feces to colonize the vagina and/or periurethral area, and then can ascend into the bladder to start a UTI. E. coli strains, including UPEC, have been sub-divided into clades (e.g., clades A, B1, B2 and D) based on their genetic relatedness. In the U.S.A, most (50-75%) UPEC fall into clade B2 while the rest (25-50%) are spread through clades A, B1, and D. Many UPEC encode a variety of putative urovirulence factor genes that are thought to enable bladder colonization and whose carriage in has been correlated with both UTI and recurrence in humans. However, in contrast to many other E. coli pathotypes and despite decades of research, a clear, genetic definition of UPEC remains elusive. Towards this goal, I pursued a research strategy integrating multiple fields of study, including large-scale bioinformatic analysis, in vitro and in vivo modeling of pathogenesis, and structural biology, within a holistic view of the UPEC evolutionary history that incorporates their residence in both the gut and the bladder. Thus, I have shown that clinical UPEC are genetically heterogeneous and that gene carriage alone is not a robust predictor of UPEC’s ability to colonize the bladder in mouse models of cystitis. Instead, I have found the transcriptional regulation of core genes shared by all E. coli strains can be used to predict the outcome of bladder infections in mice. Further, I have found that evolution has stringently conserved bacterial behaviors that are critical to both bladder and gut colonization by E. coli, namely the tension and unwinding of the type 1 pilus rod in response to shear stress. The type 1 pilus is found in the vast majority of E. coli strains and nearly every UPEC isolate and has been shown to be critical in bladder colonization in animal models of cystitis, thus underscoring the fact that bacterial features enabling uropathogenicity are common and conserved across many E. coli strains. Finally, I have shown that clade B2 UPEC have adopted genetic tools from other gut bacteria that provide them with a selective advantage in gut colonization and persistence, potentially enhancing their ability to cause recurrent UTIs. This may explain why B2 strains are enriched in UPEC overall, especially in those strains causing recurrent UTI, despite the fact that both B2 and non-B2 strains can be robust colonizers of the bladder. Taken together, these findings indicate the bladder pathogenesis may be a “core feature” of most E. coli and that the definition of UPEC may be related more to the core bacterial behaviors enabling persistence and survival in multiple body sites than any one specific virulence mechanism or carriage of certain genes. These findings extend beyond UPEC to other bacterial diseases, such as respiratory infections caused by Klebsiella or Pneumocococcus, where bacteria transition from commensal lifestyles in one habitat to pathogenic lifestyles in another body site and further work is needed to understand how conserved bacterial features may be coopted for pathogenicity in the new environment.
Chair and Committee
Scott Phillip J. Hultgren Tarr
Ashlee M. Earl, Gautam Dantas, Jeffrey P. Henderson,
Schreiber, Henry Louis, "Understanding the paradox of genetic diversity in uropathogenic E. coli: the uncommon evolution of a common pathogen" (2017). Arts & Sciences Electronic Theses and Dissertations. 1194.