Staphylococcus aureus α-toxin impairs early neutrophil localization via electrogenic disruption of store-operated calcium entry
Fan Yang,
Mingyi Suo,
Homayemem Weli,
Mason Wong,
Alex Junidi,
Celeste Cummings,
Ryan Johnson,
Kiara Mallory,
Annie Y. Liu,
Zev J. Greenberg,
Laura G. Schuettpelz,
Mark J. Miller,
Cliff J. Luke,
Gwendalyn J. Randolph,
Bernd H. Zinselmeyer,
Juliane Bubeck Wardenburg,
Regina A. Clemens
Affiliations
Fan Yang
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
Mingyi Suo
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
Homayemem Weli
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Mason Wong
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
Alex Junidi
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Celeste Cummings
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
Ryan Johnson
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
Kiara Mallory
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
Annie Y. Liu
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Zev J. Greenberg
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
Laura G. Schuettpelz
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
Mark J. Miller
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Cliff J. Luke
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
Gwendalyn J. Randolph
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Bernd H. Zinselmeyer
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Juliane Bubeck Wardenburg
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
Regina A. Clemens
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA; Corresponding author
Summary: The pore-forming S. aureus α-toxin (Hla) contributes to virulence and disease pathogenesis. While high concentrations of toxin induce cell death, neutrophils exhibit relative resistance to lysis, suggesting that the action of Hla may not be solely conferred by lytic susceptibility. Using intravital microscopy, we observed that Hla disrupts neutrophil localization and clustering early in infection. Hla forms a narrow, ion-selective pore, suggesting that Hla may dysregulate calcium or other ions to impair neutrophil function. We found that sub-lytic Hla did not permit calcium influx but caused rapid membrane depolarization. Depolarization decreases the electrogenic driving force for calcium, and concordantly, Hla suppressed calcium signaling in vitro and in vivo and calcium-dependent leukotriene B4 (LTB4) production, a key mediator of neutrophil clustering. Thus, Hla disrupts the early patterning of the neutrophil response to infection, in part through direct impairment of neutrophil calcium signaling. This early mis-localization of neutrophils may contribute to establishment of infection.
