title: Mechanisms of inflammasome activation by Vibrio cholerae secreted toxins vary with strain biotype.
abstract: Activation of inflammasomes is an important aspect of innate immune responses to bacterial infection. Recent studies have linked Vibrio cholerae secreted toxins to inflammasome activation by using murine macrophages. To increase relevance to human infection, studies of inflammasome-dependent cytokine secretion were conducted with the human THP-1 monocytic cell line and corroborated in primary human peripheral blood mononuclear cells (PBMCs). Both El Tor and classical strains of V. cholerae activated ASC (apoptosis-associated speck-like protein-containing a CARD domain)-dependent release of interleukin-1β (IL-1β) when cultured with human THP-1 cells, but the pattern of induction was distinct, depending on the repertoire of toxins the strains produced. El Tor biotype strains induced release of IL-1β dependent on NOD-like receptor family pyrin domain-containing 3 (NLRP3) and ASC due to the secreted pore-forming toxin hemolysin. Unlike in studies with mouse macrophages, the MARTX toxin did not contribute to IL-1β release from human monocytic cells. Classical biotype strains, which do not produce either hemolysin or the MARTX toxin, activated low-level IL-1β release that was induced by cholera toxin (CT) and dependent on ASC but independent of NLRP3 and pyroptosis. El Tor strains likewise showed increased IL-1β production dependent on CT when the hemolysin gene was deleted. In contrast to studies with murine macrophages, this phenotype was dependent on a catalytically active CT A subunit capable of inducing production of cyclic AMP and not on the B subunit. These studies demonstrate that the induction of the inflammasome in human THP-1 monocytes and in PBMCs by V. cholerae varies with the biotype and is mediated by both NLRP3-dependent and -independent pathways.
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Queen
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Shivani
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Jazel S
authors.initials: JS
authors.lastname: Dolores
authors.affiliation: Department of Medicine, Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Stehlik
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA k-satchell@northwestern.edu.
authors.forename: Karla J F
authors.initials: KJ
authors.lastname: Satchell
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002771:Cholera / Q000382:microbiology*; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology; D006460:Hemolysin Proteins; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D021122:Protein Subunits; D014734:Vibrio cholerae / Q000145:classification* / Q000378:metabolism*
chemical_list: D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D021122:Protein Subunits; C434464:RtxA protein, Vibrio cholerae; D008666:Metalloendopeptidases; C039814:hemagglutinin-protease
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