Strain- and host species-specific inflammasome activation, IL-1[beta] release, and cell death in macrophages infected with uropathogenic Escherichia coli

• Published in: Mucosal immunology Vol. 9; no. 1; p. 124
• Main Authors: Schaale, K, Peters, K M, Murthy, A M, Fritzsche, A K, Phan, M-d, Totsika, M, Robertson, A A B, Nichols, K B, Cooper, M A, Stacey, K J, Ulett, G C, Schroder, K, Schembri, M A, Sweet, M J
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Limited 01.01.2016
• DOI: 10.1038/mi.2015.44
• ISSN: 1933-0219

Uropathogenic Escherichia coli (UPEC) is the main etiological agent of urinary tract infections (UTIs). Little is known about interactions between UPEC and the inflammasome, a key innate immune pathway. Here we show that UPEC strains CFT073 and UTI89 trigger inflammasome activation and lytic cell death in human macrophages. Several other UPEC strains, including two multidrug-resistant ST131 isolates, did not kill macrophages. In mouse macrophages, UTI89 triggered cell death only at a high multiplicity of infection, and CFT073-mediated inflammasome responses were completely NLRP3-dependent. Surprisingly, CFT073- and UTI89-mediated responses only partially depended on NLRP3 in human macrophages. In these cells, NLRP3 was required for interleukin-1β (IL-1β) maturation, but contributed only marginally to cell death. Similarly, caspase-1 inhibition did not block cell death in human macrophages. In keeping with such differences, the pore-forming toxin α-hemolysin mediated a substantial proportion of CFT073-triggered IL-1β secretion in mouse but not human macrophages. There was also a more substantial α-hemolysin-independent cell death response in human vs. mouse macrophages. Thus, in mouse macrophages, CFT073-triggered inflammasome responses are completely NLRP3-dependent, and largely α-hemolysin-dependent. In contrast, UPEC activates an NLRP3-independent cell death pathway and an α-hemolysin-independent IL-1β secretion pathway in human macrophages. This has important implications for understanding UTI in humans.