Uropathogenic E. coli subverts innate immune function of bladder epithelial cells

Abstract

Urinary tract infections (UTI) are a serious cause of morbidity in the United States. Although uropathogenic E. coli (UPEC) accounts for 80–90% of UTI, UPEC colonization of the bladder is poorly understood. We hypothesize that evasion of the immune response plays a role in UPEC pathogenesis. Co‐culture of T24 bladder epithelial cells with non‐pathogenic E. coli (NPEC) resulted in induction of IL6 secretion, whereas UPEC co‐culture did not. A mixed UPEC/NPEC culture reduced IL6 secretion by T24 cells at least two‐fold compared to NPEC alone, suggesting that the inhibitory effect is dominant. To test this possibility, we exposed T24 cells to a mixture of UPEC and Toll‐like receptor (TLR) agonists. We found that UPEC reduced IL6 secretion in response to FSL‐1, Poly(I:C), and lipopolysaccharide (LPS). One possible mechanism of suppression is that UPEC LPS antagonizes TLR4 signaling. However, we found that LPS purified from both NPEC and UPEC induced secretion of IL6 to similar levels, and expression of a dominant negative TLR4 allele had no effect on inhibition. UPEC actively suppresses innate immune function in bladder epithelial cells, preventing secretion of cytokines in response to the bacteria themselves or to other TLR stimuli. This suppression is at least partially mediated by an LPS‐ and TLR4‐independent pathway. Subversion of the innate immune response likely plays an important role in UPEC pathogenesis.