Innate Transcriptional Networks Activated in Bladder in Response to Uropathogenic Escherichia coli Drive Diverse Biological Pathways and Rapid Synthesis of IL-10 for Defense against Bacterial Urinary Tract Infection

Abstract

Early transcriptional activation events that occur in bladder immediately following bacterial urinary tract infection (UTI) are not well defined. In this study, we describe the whole bladder transcriptome of uropathogenic Escherichia coli (UPEC) cystitis in mice using genome-wide expression profiling to define the transcriptome of innate immune activation stemming from UPEC colonization of the bladder. Bladder RNA from female C57BL/6 mice, analyzed using 1.0 ST-Affymetrix microarrays, revealed extensive activation of diverse sets of innate immune response genes, including those that encode multiple IL-family members, receptors, metabolic regulators, MAPK activators, and lymphocyte signaling molecules. These were among 1564 genes differentially regulated at 2 h postinfection, highlighting a rapid and broad innate immune response to bladder colonization. Integrative systems-level analyses using InnateDB (http://www.innatedb.com) bioinformatics and ingenuity pathway analysis identified multiple distinct biological pathways in the bladder transcriptome with extensive involvement of lymphocyte signaling, cell cycle alterations, cytoskeletal, and metabolic changes. A key regulator of IL activity identified in the transcriptome was IL-10, which was analyzed functionally to reveal marked exacerbation of cystitis in IL-10–deficient mice. Studies of clinical UTI revealed significantly elevated urinary IL-10 in patients with UPEC cystitis, indicating a role for IL-10 in the innate response to human UTI. The whole bladder transcriptome presented in this work provides new insight into the diversity of innate factors that determine UTI on a genome-wide scale and will be valuable for further data mining. Identification of protective roles for other elements in the transcriptome will provide critical new insight into the complex cascade of events that underpin UTI.

Discovery and Characterization of Human-Urine Utilization by Asymptomatic-Bacteriuria-Causing Streptococcus agalactiae

“…More broadly, the literature shows that ABU-causing E. coli strains bind poorly to urothelial cells and fail to stimulate a strong proinflammatory response during persistent infection (24,25,32,(63)(64)(65). In contrast, uropathogenic bacteria adhere to urothelial cells and induce inflammation (34,66,67). Prior studies showed that UPSA can adhere to urothelial cells efficiently; however, UPSA grew poorly in urine (33,34), consistent with a report by Stamey and Mihara (35).…”

Spectrum of Bacterial Colonization Associated with Urothelial Cells from Patients with Chronic Lower Urinary Tract Symptoms

“…Hannan et al (37) showed that inflammatory events in the bladder during early uropathogenic E. coli (UPEC) infections in mice predisposed the mice to subsequent susceptibility to recurrent infections. Two genomewide transcriptomic studies, by Duell et al (38) and Tan et al (39), have provided insights into the factors that might contribute to innate resistance to UPEC and have shown that bladder inflammation in response to UPEC is pathogen-specific and that UPEC somehow harnesses complex innate immune responses in the bladder to promote bacterial survival and a predisposition to chronicity.…”

Cytotoxic Necrotizing Factor 1 and Hemolysin from Uropathogenic Escherichia coli Elicit Different Host Responses in the Murine Bladder

“…Microarray analyses of host RNA isolated from the bladders of UPEC-challenged mice at various times postinoculation have identified numerous cellular pathways that are altered in the presence of UPEC (30)(31)(32). Common themes among these studies are that the bladder transcriptional response to UPEC occurs rapidly and that it is dominated by genes that function in proinflammatory, prosurvival, and antiapoptotic pathways.…”