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

Staphylococcus aureus Leukocidins Target Endothelial DARC to Cause Lethality in Mice.

Author information

1
Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
2
Keenan Research Centre, St Michael's Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada. Electronic address: leew@smh.ca.
3
Keenan Research Centre, St Michael's Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada.
4
Janssen Research & Development LLC, 1400 McKean Road, Spring House, PA 19477, USA.
5
Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA; Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.
6
Department of Pathology, New York University School of Medicine, New York, NY, USA.
7
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
8
Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.
9
Department of Pathology, New York University School of Medicine, New York, NY, USA; Office of Collaborative Sciences, NYU School of Medicine, New York, NY, USA; Department of Pathology, NYU School of Medicine, New York, NY, USA.
10
Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA; Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
11
Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA; Division of Infectious Diseases, Department of Medicine, NYU School of Medicine, New York, NY 10016, USA.
12
Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: victor.torres@nyulangone.org.

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.

KEYWORDS:

ACKR1; DARC; HlgAB; LukED; Staphylococcus aureus; endothelial cells; leukocidin

PMID:
30799265
PMCID:
PMC6468323
[Available on 2020-03-13]
DOI:
10.1016/j.chom.2019.01.015

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