Title | Metabolic Stress Drives Keratinocyte Defenses against Staphylococcus aureus Infection. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Wickersham M, Wachtel S, Lung TWong Fok, Soong G, Jacquet R, Richardson A, Parker D, Prince A |
Journal | Cell Rep |
Volume | 18 |
Issue | 11 |
Pagination | 2742-2751 |
Date Published | 2017 03 14 |
ISSN | 2211-1247 |
Keywords | Animals, Cell Line, Cytokines, Glycolysis, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Keratinocytes, Mice, Inbred C57BL, Oxygen Consumption, Signal Transduction, Skin, Staphylococcal Infections, Staphylococcus aureus, Stress, Physiological |
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. |
DOI | 10.1016/j.celrep.2017.02.055 |
Alternate Journal | Cell Rep |
PubMed ID | 28297676 |
PubMed Central ID | PMC6799992 |
Grant List | R01 AI103854 / AI / NIAID NIH HHS / United States R01 HL079395 / HL / NHLBI NIH HHS / United States S10 RR027050 / RR / NCRR NIH HHS / United States P30 CA013696 / CA / NCI NIH HHS / United States |
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