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S. aureus induction of Hif1α drives airway epithelial inflammatory signaling
Author(s) -
Jurado Andrea,
Wickersham Matthew,
Lung Tania Wong Fok,
Miller Alex,
Parker Dane,
Prince Alice
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb759
Subject(s) - glycolysis , staphylococcus aureus , biology , microbiology and biotechnology , hif1a , immune system , signal transduction , secretion , immunology , cancer research , biochemistry , metabolism , angiogenesis , bacteria , genetics
RATIONALE Staphylococcus aureus is a major cause of healthcare associated pneumonia and leads to high morbidity and mortality rates. Immune cells depend on glycolysis, particularly through Hif1α signaling, to drive pro‐inflammatory defenses to clear bacterial infections. We postulated that airway epithelial cells similarly use Hif1α stabilization and glycolysis to defend against S. aureus infection. METHODS A proteomic analysis of bronchoalveolar lavage fluid (BALF) from S. aureus USA300 infected C57BL/6 mice was performed comparing infected and uninfected mice. The metabolic and immunological consequences of Hif1a signaling were demonstrated in vitro. Human bronchial epithelial (16HBE) cells were studied through qRT arrays, western blots and ELISAs. RESULTS S. aureus wild type USA300 (WT) were found to activate the canonical Hif1a and metabolic pathways that support glycolysis, as defined by the Ingenuity Pathway Analysis (IPA) of the secreted proteins in the BALF of infected mice. These results were verified in immunoblots demonstrating that S. aureus WT and toxin‐deficient agr mutants both stabilize Hif1α in 16HBE cells, despite significantly increased intracellular accumulation of the agr strain. Increased Hif1α corresponded with increased IL‐1b, IL‐8 and phosphofructokinase 1 (PFK1) transcript levels under infected conditions. The induction of HIF1a signaling, as a consequence of the metabolic stress caused by infection, was dependent on the glycolytic capacities of the bacteria, as a glycolytic mutant of S. aureus lacking pyruvate kinase ( pyk ) failed to induce Hif1α or secrete pro‐inflammatory cytokines IL‐1β and IL‐18. This was in contrast to WT and phosphoenolpyruvate kinase ( pckA ) deficient strains, with impaired gluconeogenesis. CONCLUSIONS The induction of epithelial glycolysis contributes to the metabolic and inflammatory response to S. aureus pulmonary infection. Both the organisms and the host use glycolysis to meet their increased metabolic requirements, promoting competition for glucose and stimulating Hif1a signaling. Our data highlights that metabolic stress is a driving factor in the host response to S. aureus in the lung, suggesting that manipulating metabolism might be a novel approach in the prevention and treatment of bacterial pneumonia. Support or Funding Information FUNDING: NIH R35 HL135300