E. coli virulence gene expression during clinical UTIs in women

了解尿路致病性大肠埃希菌引起尿路感染的发病机制

To understand the pathogenesis of urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC), it is critical to both follow up on our determination of the transcriptional program enacted by UPEC during uncomplicated UTI in young women and to understand similarities and differences in host-pathogen interactions in young versus postmenopausal patients. This allows insights from prior studies in young women to be directly applied to the older population. We will model infection from initial colonization to development of acute infection in the bladder to identify mechanisms that induce rapid growth of UPEC. In addition, there are no studies defining the transcriptional program of UPEC strains that infect postmenopausal women, a critical high impact cohort that commonly suffers from recurrent UTI (rUTI). Indeed, UTIs are responsible for 15.5% of hospitalizations and 6.2% of deaths in women over 65 years old. It is vital to compare patterns of UPEC gene expression between these two groups of patients who present with dramatically different bladder milieus. Our long-term research goal is to understand how UPEC colonizes the human urinary tract, eludes the immune response, and damages the host. The objective during this funding period is to follow up on our transcriptome studies in uncomplicated UTIs, understanding how gene expression is deployed over time and assess the UPEC transcriptome in postmenopausal women to monitor bacterial factors important for development of infection, Our central hypothesis is that the end point of urinary tract infection is a consequence of sequential host-pathogen interactions, wherein UPEC enacts a highly conserved regulatory program in response to its encounter with the host. The rationale for the proposed work is that once we identify the transcriptional program of UPEC during early stages of colonization, we can focus efforts on intervention and prevention directed toward these specific targets. We will test our central hypothesis and complete our objectives by carrying out two specific aims: 1) Determine the temporal gene expression program of UPEC in the urinary tract from initiation to development of acute infection of the bladder using the mouse model of ascending UTI and elucidate the molecular mechanism that induces rapid growth of UPEC in the urinary tract. 2) Determine the transcriptomes and growth rates of UPEC during UTI in postmenopausal women. Expected outcomes will be a temporal assessment of global UPEC gene expression during UTI and a measure of UPEC gene expression in postmenopausal women. Expression of all UPEC genes will be followed over time using UPEC strains isolated from young patients in the validated mouse UTI model. Metabolites that trigger rapid growth rates will be identified in patients and mice. The positive impact of these studies will be to pave the way to disease prevention by understanding the progression of gene expression over time during UTI and identifying metabolites that accentuate infection in UTI. Understanding specific virulence factors and core genes expressed by UPEC will allow development of specific therapeutics against novel targets.