title: Metabolic Stress Drives Keratinocyte Defenses against Staphylococcus aureus Infection.
abstract: Human skin is commonly colonized and infected by Staphylococcus aureus. Exactly how these organisms are sensed by keratinocytes has not been clearly delineated. Using a combination of metabolic and transcriptomic methodologies, we found that S. aureus infection is sensed as a metabolic stress by the hypoxic keratinocytes. This induces HIF1α signaling, which promotes IL-1β production and stimulates aerobic glycolysis to meet the metabolic requirements of infection. We demonstrate that staphylococci capable of glycolysis, including WT and agr mutants, readily induce HIF1α responses. In contrast, Δpyk glycolytic mutants fail to compete with keratinocytes for their metabolic needs. Suppression of glycolysis using 2-DG blocked keratinocyte production of IL-1β in vitro and significantly exacerbated the S. aureus cutaneous infection in a murine model. Our data suggest that S. aureus impose a metabolic stress on keratinocytes that initiates signaling necessary to promote both glycolysis and the proinflammatory response to infection.
authors.affiliation: Deparment of Pediatrics, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wickersham
authors.affiliation: Deparment of Pediatrics, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wachtel
authors.affiliation: Deparment of Pediatrics, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Tania
authors.initials: T
authors.lastname: Wong Fok Lung
authors.affiliation: Deparment of Pediatrics, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Soong
authors.affiliation: Deparment of Pediatrics, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Rudy
authors.initials: R
authors.lastname: Jacquet
authors.affiliation: Department of Microbiology & Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Richardson
authors.affiliation: Deparment of Pediatrics, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Dane
authors.initials: D
authors.lastname: Parker
authors.affiliation: Deparment of Pediatrics, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA. Electronic address: asp7@cumc.columbia.edu.
authors.forename: Alice
authors.initials: A
authors.lastname: Prince
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D015603:Keratinocytes / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D008810:Mice, Inbred C57BL; D010101:Oxygen Consumption; D015398:Signal Transduction; D012867:Skin / Q000382:microbiology / Q000473:pathology; D013203:Staphylococcal Infections / Q000276:immunology* / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000502:physiology*; D013312:Stress, Physiological
chemical_list: D016207:Cytokines; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: HIF1α; Staphylococcus aureus; glycolysis; immunometabolism; keratinocytes