title: Staphylococcus aureus Leukocidin A/B (LukAB) Kills Human Monocytes via Host NLRP3 and ASC when Extracellular, but Not Intracellular.
abstract: Staphylococcus aureus infections are a growing health burden worldwide, and paramount to this bacterium's pathogenesis is the production of virulence factors, including pore-forming leukotoxins. Leukocidin A/B (LukAB) is a recently discovered toxin that kills primary human phagocytes, though the underlying mechanism of cell death is not understood. We demonstrate here that LukAB is a major contributor to the death of human monocytes. Using a variety of in vitro and ex vivo intoxication and infection models, we found that LukAB activates Caspase 1, promotes IL-1β secretion and induces necrosis in human monocytes. Using THP1 cells as a model for human monocytes, we found that the inflammasome components NLRP3 and ASC are required for LukAB-mediated IL-1β secretion and necrotic cell death. S. aureus was shown to kill human monocytes in a LukAB dependent manner under both extracellular and intracellular ex vivo infection models. Although LukAB-mediated killing of THP1 monocytes from extracellular S. aureus requires ASC, NLRP3 and the LukAB-receptor CD11b, LukAB-mediated killing from phagocytosed S. aureus is independent of ASC or NLRP3, but dependent on CD11b. Altogether, this study provides insight into the nature of LukAB-mediated killing of human monocytes. The discovery that S. aureus LukAB provokes differential host responses in a manner dependent on the cellular contact site is critical for the development of anti-infective/anti-inflammatory therapies that target the NLRP3 inflammasome.
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Melehani
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: David B A
authors.initials: DB
authors.lastname: James
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Ashley L
authors.initials: AL
authors.lastname: DuMont
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Torres
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Department of Medicine, Division of Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Duncan
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism*; D005434:Flow Cytometry; D006790:Host-Parasite Interactions / Q000502:physiology*; D006801:Humans; D007118:Immunoassay; D015151:Immunoblotting; D042541:Intracellular Space / Q000378:metabolism; D007956:Leukocidins / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D013203:Staphylococcal Infections / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000378:metabolism; D037521:Virulence Factors / Q000502:physiology*
chemical_list: D001426:Bacterial Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D007956:Leukocidins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C402202:PYCARD protein, human; D037521:Virulence Factors; C586430:leukocidin AB, Staphylococcus aureus