Urinary Tract InfectionUPEC genomics/geneticsChaperone/Usher Pathway PiliEnterococcal pathogenesis/catheter-associated UTIBacterial amyloid (Curli) biogenesisBacterial Community Interactions (Biofilms and Microbiome)Drug and Vaccine Development

Uropathogenic E. coli (UPEC) genomics/genetics

UPEC are highly diverse. It has been well established that E. coli has a highly plastic genome capable of rapid alteration to facilitate survival in diverse environments. In addition, the role of host anatomy, physiology, and immune response may dramatically impact the susceptibility of individual strains of E. coli to colonize the host. Because of these factors, no specific genome structure or content has been identified that serves as a signature for the ability of E. coli to cause UTI.

We have completed the full genome sequence of multiple urinary and fecal E. coli isolates and are analyzing this data to better understand UPEC pathogenesis requirements. From a clinical study following women with a history of rUTI histories we sequenced 43 rUTI UPEC isolates. We conducted a comparative genomic analysis of these strains along with a set of 46 reference E. coli genomes including 7 additional UPEC and 39 non-UPEC genomes from E. coli isolated from other body sites. We defined a pan-genome of 12,341 genes and a core genome of 2,923 genes shared by all 89 strains. However, we were unable to identify a single set of genes that clearly discriminated UPEC from non-UPEC strains. Interestingly, we did show that colonization success of E. coli in experimental mouse models of UTI could be predicted by the transcriptional state of the core genomes of isolates after growth in in vitro conditions. Further, we have shown that UPEC has evolved particular protein coding changes under positive selection for alleles that best function in the urinary tract environment. For instance, we determined that different fimH alleles are selected for in UPEC strains vs. non-UPEC strains, leading to the elucidation of an important protein conformational equilibrium of FimH that is critical for its function in the urinary tract. We also identified 29 other positively selected protein coding genes, each with distinct signatures within UPEC strains. Eight of these genes are required for establishment and maintenance of chronic cystitis.

Using a blend of comparative genomics and transcriptomics, and molecular evolution studies, we are looking for functional genes, regulatory programs and positively selected gene sequences that enable E. coli to cause disease in the urinary tract and exist within the gut. More extensive characterizations of strains from patients with differing disease syndromes will lead to a better understanding of the UPEC pathoadaptations which promote UTI occurrence.

Collaborators: Ann Stapleton, Jeff Gordon, Swaine Chen, Ashlee Earl