title: Strain- and host species-specific inflammasome activation, IL-1β release, and cell death in macrophages infected with uropathogenic Escherichia coli.
abstract: 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.
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia.|Australian Infectious Diseases Research Centre, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Schaale
authors.affiliation: Australian Infectious Diseases Research Centre, University of Queensland, St Lucia, Queensland, Australia.|School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: K M
authors.initials: KM
authors.lastname: Peters
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: A M
authors.initials: AM
authors.lastname: Murthy
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: A K
authors.initials: AK
authors.lastname: Fritzsche
authors.affiliation: Australian Infectious Diseases Research Centre, University of Queensland, St Lucia, Queensland, Australia.|School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: M-D
authors.initials: MD
authors.lastname: Phan
authors.affiliation: Australian Infectious Diseases Research Centre, University of Queensland, St Lucia, Queensland, Australia.|Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Kelvin Grove, Queensland, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Totsika
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia.|Australian Infectious Diseases Research Centre, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: A A B
authors.initials: AA
authors.lastname: Robertson
authors.affiliation: Australian Infectious Diseases Research Centre, University of Queensland, St Lucia, Queensland, Australia.|School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: K B
authors.initials: KB
authors.lastname: Nichols
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia.|Australian Infectious Diseases Research Centre, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: M A
authors.initials: MA
authors.lastname: Cooper
authors.affiliation: Australian Infectious Diseases Research Centre, University of Queensland, St Lucia, Queensland, Australia.|School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: K J
authors.initials: KJ
authors.lastname: Stacey
authors.affiliation: School of Medical Sciences, Griffith Health Institute, Griffith University, Gold Coast, Queensland, Australia.
authors.forename: G C
authors.initials: GC
authors.lastname: Ulett
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia.|Australian Infectious Diseases Research Centre, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Schroder
authors.affiliation: Australian Infectious Diseases Research Centre, University of Queensland, St Lucia, Queensland, Australia.|School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: M A
authors.initials: MA
authors.lastname: Schembri
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia.|Australian Infectious Diseases Research Centre, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Sweet
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D016923:Cell Death / Q000187:drug effects; D005786:Gene Expression Regulation; D006460:Hemolysin Proteins / Q000633:toxicity; D054884:Host-Pathogen Interactions; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects* / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D061251:Primary Cell Culture; D015398:Signal Transduction; D013045:Species Specificity; D056689:Uropathogenic Escherichia coli / Q000276:immunology* / Q000472:pathogenicity
chemical_list: D001427:Bacterial Toxins; D002352:Carrier Proteins; D006460:Hemolysin Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; C021091:staphylococcal alpha-toxin