Staphylococcus aureus α-toxin impairs early neutrophil localization via electrogenic disruption of store-operated calcium entry

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. [Display omitted] •S. aureus α-toxin disrupts the cell membrane potential to impair neutrophil SOCE•S. aureus α-toxin impairs neutrophil localization and clustering at sites of infection•Neutrophil mis-localization correlates with impaired bacterial control Yang et al. find that the pore-forming S. aureus α-toxin (Hla) disrupts the neutrophil response to infection by impairing calcium signaling. Acting as an ion-selective channel, Hla permits sodium influx leading to membrane depolarization and decreased electrogenic driving force for calcium entry. Mis-localization of neutrophils correlates with impaired bacterial control.