Staphylococcus aureus Leukocidins Target Endothelial DARC to Cause Lethality in Mice

Cell Host Microbe. 2019 Mar 13;25(3):463-470.e9. doi: 10.1016/j.chom.2019.01.015. Epub 2019 Feb 21.


The pathogenesis of Staphylococcus aureus is thought to depend on the production of pore-forming leukocidins that kill leukocytes and lyse erythrocytes. Two leukocidins, Leukocidin ED (LukED) and γ-Hemolysin AB (HlgAB), are necessary and sufficient to kill mice upon infection and toxin challenge. We demonstrate that LukED and HlgAB cause vascular congestion and derangements in vascular fluid distribution that rapidly cause death in mice. The Duffy antigen receptor for chemokines (DARC) on endothelial cells, rather than leukocytes or erythrocytes, is the critical target for lethality. Consistent with this, LukED and HlgAB injure primary human endothelial cells in a DARC-dependent manner, and mice with DARC-deficient endothelial cells are resistant to toxin-mediated lethality. During bloodstream infection in mice, DARC targeting by S. aureus causes increased tissue damage, organ dysfunction, and host death. The potential for S. aureus leukocidins to manipulate vascular integrity highlights the importance of these virulence factors.

Keywords: ACKR1; DARC; HlgAB; LukED; Staphylococcus aureus; endothelial cells; leukocidin.

MeSH terms

  • Animals
  • Bacterial Proteins / metabolism
  • Bacterial Proteins / toxicity*
  • Bacterial Toxins / metabolism
  • Bacterial Toxins / toxicity*
  • Cell Survival / drug effects
  • Cells, Cultured
  • Disease Models, Animal
  • Duffy Blood-Group System / metabolism*
  • Endothelial Cells / drug effects*
  • Exotoxins / metabolism
  • Exotoxins / toxicity*
  • Hemolysin Proteins / metabolism
  • Hemolysin Proteins / toxicity*
  • Humans
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Receptors, Cell Surface / metabolism*
  • Staphylococcal Infections / pathology*
  • Staphylococcus aureus / metabolism
  • Staphylococcus aureus / pathogenicity*
  • Survival Analysis


  • ACKR1 protein, human
  • Bacterial Proteins
  • Bacterial Toxins
  • Duffy Blood-Group System
  • Exotoxins
  • Hemolysin Proteins
  • LukD protein, Staphylococcus aureus
  • LukE protein, Staphylococcus aureus
  • Receptors, Cell Surface
  • gamma-hemolysin, Staphylococcus aureus