Abstract
The NLRP3 inflammasome and IL-1β release have recently been suggested to be important for the progression of urinary tract infection (UTI). However, much is still unknown regarding the interaction of UPEC and the NLRP3 inflammasome. The purpose of this study was to elucidate what virulence factors uropathogenic Escherichia coli (UPEC) use to modulate NLRP3 inflammasome activation and subsequent IL-1β release and the role of NLRP3 for UPEC colonization of bladder epithelial cells. The bladder epithelial cell line 5637, CRISPR/Cas9 generated NLRP3, caspase-1 and mesotrypsin deficient cell lines and transformed primary bladder epithelial cells (HBLAK) were stimulated with UPEC isolates and the non-pathogenic MG1655 strain. We found that the UPEC strain CFT073, but not MG1655, induced an increased caspase-1 activity and IL-1β release from bladder epithelial cells. The increase was shown to be mediated by α-hemolysin activation of the NLRP3 inflammasome in an NF-κB-independent manner. The effect of α-hemolysin on IL-1β release was biphasic, initially suppressive, later inductive. Furthermore, the phase-locked type-1-fimbrial ON variant of CFT073 inhibited caspase-1 activation and IL-1β release. In addition, the ability of CFT073 to adhere to and invade NLRP3 deficient cells was significantly reduced compare to wild-type cells. The reduced colonization of NLRP3-deficient cells was type-1 fimbriae dependent. In conclusion, we found that the NLRP3 inflammasome was important for type-1 fimbriae-dependent colonization of bladder epithelial cells and that both type-1 fimbriae and α-hemolysin can modulate the activity of the NLRP3 inflammasome.
Highlights
Urinary tract infection (UTI), the majority caused by uropathogenic E. coli (UPEC), is one of the most common human infections and 60% of all women are expected to report at least one episode of UTI during their lifetime
Recent studies have suggested that the NACHT leucin-rich repeat PYD protein 3 (NLRP3) inflammasome and IL-1β are important for the establishment and progression of a UTI (Nagamatsu et al, 2015; Symington et al, 2015; Ambite et al, 2016)
We showed that the UPEC strain CFT073, but not the non-pathogenic MG1655, induced an increased IL-1β release from bladder epithelial cells accompanied by an increased caspase-1 activation and increased epithelial cell death
Summary
Urinary tract infection (UTI), the majority caused by uropathogenic E. coli (UPEC), is one of the most common human infections and 60% of all women are expected to report at least one episode of UTI during their lifetime. Genomic analysis have identified considerable differences between UPEC isolates, making it difficult to pinpoint specific virulence factors associated with successful colonization of the urinary tract (Marrs et al, 2005; Lo et al, 2015) Virulence factors such as lipopolysaccharide (LPS), toll/interleukin-1 receptor domain-containing protein (TcpC), siderophores (iron scavenger system), α-hemolysin, type-1-and P-fimbriae and capsular have been shown to play a role in the infection during a UTI (Bower et al, 2005; Yadav et al, 2010; Bien et al, 2012). Α-hemolysin has a more immunomodulating effect and promotes exfoliation of bladder epithelial cells, whereas at high concentration, the toxin lyses epithelial and immune cells which enables UPEC to access nutrients and iron from host cells (Dhakal and Mulvey, 2012; Ristow and Welch, 2016) It is the interplay of several virulence factors that makes UPEC a successful colonizer of the urinary tract. The ability of UPEC to form protective intracellular reservoirs has been associated with host evasion and recurrent UTI (Rosen et al, 2007; Andersen et al, 2012; Hannan et al, 2012)
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