1. Staphylococcus aureus Leukocidins Target Endothelial DARC to Cause Lethality in Mice.
- Author
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Lubkin A, Lee WL, Alonzo F 3rd, Wang C, Aligo J, Keller M, Girgis NM, Reyes-Robles T, Chan R, O'Malley A, Buckley P, Vozhilla N, Vasquez MT, Su J, Sugiyama M, Yeung ST, Coffre M, Bajwa S, Chen E, Martin P, Kim SY, Loomis C, Worthen GS, Shopsin B, Khanna KM, Weinstock D, Lynch AS, Koralov SB, Loke P, Cadwell K, and Torres VJ
- Subjects
- Animals, Bacterial Proteins metabolism, Bacterial Toxins metabolism, Cell Survival drug effects, Cells, Cultured, Disease Models, Animal, Exotoxins metabolism, Hemolysin Proteins metabolism, Humans, Mice, Mice, Knockout, Models, Biological, Staphylococcus aureus metabolism, Survival Analysis, Bacterial Proteins toxicity, Bacterial Toxins toxicity, Duffy Blood-Group System metabolism, Endothelial Cells drug effects, Exotoxins toxicity, Hemolysin Proteins toxicity, Receptors, Cell Surface metabolism, Staphylococcal Infections pathology, Staphylococcus aureus pathogenicity
- Abstract
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., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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