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

Mucosal Immunol. 2016 Jan;9(1):124-36. doi: 10.1038/mi.2015.44. Epub 2015 May 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Toxins / toxicity
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Cell Death / drug effects
  • Gene Expression Regulation
  • Hemolysin Proteins / toxicity
  • Host-Pathogen Interactions
  • Humans
  • Inflammasomes / drug effects*
  • Inflammasomes / immunology
  • Interleukin-1beta / genetics
  • Interleukin-1beta / immunology*
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Macrophages / microbiology
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Primary Cell Culture
  • Signal Transduction
  • Species Specificity
  • Uropathogenic Escherichia coli / immunology*
  • Uropathogenic Escherichia coli / pathogenicity


  • Bacterial Toxins
  • Carrier Proteins
  • Hemolysin Proteins
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nlrp3 protein, mouse
  • staphylococcal alpha-toxin