Human CD45 is an f-component-specific receptor for the staphylococcal toxin Panton-Valentine leukocidin

Angelino T. Tromp; Michiel Van Gent; Pauline Abrial; Amandine Martin; Joris P. Jansen; Carla J.C. De Haas; Kok P.M. Van Kessel; Bart W. Bardoel; Elisabeth Kruse; Emilie Bourdonnay; Michael Boettcher; Michael T. McManus; Christopher J. Day; Michael P. Jennings; Gérard Lina; François Vandenesch; Jos A.G. Van Strijp; Robert Jan Lebbink; Pieter Jan A. Haas; Thomas Henry; András N. Spaan

doi:10.1038/s41564-018-0159-x

Human CD45 is an f-component-specific receptor for the staphylococcal toxin Panton-Valentine leukocidin

Angelino T. Tromp
, Michiel Van Gent
, Pauline Abrial
, Amandine Martin
, Joris P. Jansen
, Carla J.C. De Haas
, Kok P.M. Van Kessel
, Bart W. Bardoel
, Elisabeth Kruse
, Emilie Bourdonnay
, Michael Boettcher
, Michael T. McManus
, Christopher J. Day
, Michael P. Jennings
, Gérard Lina
, François Vandenesch
, Jos A.G. Van Strijp
, Robert Jan Lebbink
, Pieter Jan A. Haas
, Thomas Henry^*

András N. Spaan

^*Corresponding author for this work

Utrecht University
University Medical Centre Utrecht
The University of Chicago
Universite Claude Bernard Lyon 1
University of California at San Francisco
Griffith University Queensland
Rockefeller University

Research output: Contribution to journal › Article › Academic › peer-review

75 Citations (Scopus)

Abstract

The staphylococcal bi-component leukocidins Panton-Valentine leukocidin (PVL) and γ-haemolysin CB (HlgCB) target human phagocytes. Binding of the toxins' S-components to human complement C5a receptor 1 (C5aR1) contributes to cellular tropism and human specificity of PVL and HlgCB. To investigate the role of both leukocidins during infection, we developed a human C5aR1 knock-in (hC5aR1 ^KI ) mouse model. HlgCB, but unexpectedly not PVL, contributed to increased bacterial loads in tissues of hC5aR1 ^KI mice. Compared to humans, murine hC5aR1 ^KI neutrophils showed a reduced sensitivity to PVL, which was mediated by the toxin's F-component LukF-PV. By performing a genome-wide CRISPR-Cas9 screen, we identified CD45 as a receptor for LukF-PV. The human-specific interaction between LukF-PV and CD45 provides a molecular explanation for resistance of hC5aR1 ^KI mouse neutrophils to PVL and probably contributes to the lack of a PVL-mediated phenotype during infection in these mice. This study demonstrates an unsuspected role of the F-component in driving the sensitivity of human phagocytes to PVL.

Original language	English
Pages (from-to)	708-717
Number of pages	10
Journal	Nature Microbiology
Volume	3
Issue number	6
DOIs	https://doi.org/10.1038/s41564-018-0159-x
Publication status	Published - 1 Jun 2018
Externally published	Yes

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Tromp, A. T., Van Gent, M., Abrial, P., Martin, A., Jansen, J. P., De Haas, C. J. C., Van Kessel, K. P. M., Bardoel, B. W., Kruse, E., Bourdonnay, E., Boettcher, M., McManus, M. T., Day, C. J., Jennings, M. P., Lina, G., Vandenesch, F., Van Strijp, J. A. G., Jan Lebbink, R., Haas, P. J. A., ... Spaan, A. N. (2018). Human CD45 is an f-component-specific receptor for the staphylococcal toxin Panton-Valentine leukocidin. Nature Microbiology, 3(6), 708-717. https://doi.org/10.1038/s41564-018-0159-x

@article{0cbbd361f1bd4fb4aaa2ecdf5fa1fd13,

title = "Human CD45 is an f-component-specific receptor for the staphylococcal toxin Panton-Valentine leukocidin",

abstract = " The staphylococcal bi-component leukocidins Panton-Valentine leukocidin (PVL) and γ-haemolysin CB (HlgCB) target human phagocytes. Binding of the toxins' S-components to human complement C5a receptor 1 (C5aR1) contributes to cellular tropism and human specificity of PVL and HlgCB. To investigate the role of both leukocidins during infection, we developed a human C5aR1 knock-in (hC5aR1 KI ) mouse model. HlgCB, but unexpectedly not PVL, contributed to increased bacterial loads in tissues of hC5aR1 KI mice. Compared to humans, murine hC5aR1 KI neutrophils showed a reduced sensitivity to PVL, which was mediated by the toxin's F-component LukF-PV. By performing a genome-wide CRISPR-Cas9 screen, we identified CD45 as a receptor for LukF-PV. The human-specific interaction between LukF-PV and CD45 provides a molecular explanation for resistance of hC5aR1 KI mouse neutrophils to PVL and probably contributes to the lack of a PVL-mediated phenotype during infection in these mice. This study demonstrates an unsuspected role of the F-component in driving the sensitivity of human phagocytes to PVL.",

author = "Tromp, \{Angelino T.\} and \{Van Gent\}, Michiel and Pauline Abrial and Amandine Martin and Jansen, \{Joris P.\} and \{De Haas\}, \{Carla J.C.\} and \{Van Kessel\}, \{Kok P.M.\} and Bardoel, \{Bart W.\} and Elisabeth Kruse and Emilie Bourdonnay and Michael Boettcher and McManus, \{Michael T.\} and Day, \{Christopher J.\} and Jennings, \{Michael P.\} and G{\'e}rard Lina and Fran{\c c}ois Vandenesch and \{Van Strijp\}, \{Jos A.G.\} and \{Jan Lebbink\}, Robert and Haas, \{Pieter Jan A.\} and Thomas Henry and Spaan, \{Andr{\'a}s N.\}",

note = "Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = jun,

day = "1",

doi = "10.1038/s41564-018-0159-x",

language = "English",

volume = "3",

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journal = "Nature Microbiology",

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Tromp, AT, Van Gent, M, Abrial, P, Martin, A, Jansen, JP, De Haas, CJC, Van Kessel, KPM, Bardoel, BW, Kruse, E, Bourdonnay, E, Boettcher, M, McManus, MT, Day, CJ, Jennings, MP, Lina, G, Vandenesch, F, Van Strijp, JAG, Jan Lebbink, R, Haas, PJA, Henry, T & Spaan, AN 2018, 'Human CD45 is an f-component-specific receptor for the staphylococcal toxin Panton-Valentine leukocidin', Nature Microbiology, vol. 3, no. 6, pp. 708-717. https://doi.org/10.1038/s41564-018-0159-x

TY - JOUR

T1 - Human CD45 is an f-component-specific receptor for the staphylococcal toxin Panton-Valentine leukocidin

AU - Tromp, Angelino T.

AU - Van Gent, Michiel

AU - Abrial, Pauline

AU - Martin, Amandine

AU - Jansen, Joris P.

AU - De Haas, Carla J.C.

AU - Van Kessel, Kok P.M.

AU - Bardoel, Bart W.

AU - Kruse, Elisabeth

AU - Bourdonnay, Emilie

AU - Boettcher, Michael

AU - McManus, Michael T.

AU - Day, Christopher J.

AU - Jennings, Michael P.

AU - Lina, Gérard

AU - Vandenesch, François

AU - Van Strijp, Jos A.G.

AU - Jan Lebbink, Robert

AU - Haas, Pieter Jan A.

AU - Henry, Thomas

AU - Spaan, András N.

PY - 2018/6/1

Y1 - 2018/6/1

N2 - The staphylococcal bi-component leukocidins Panton-Valentine leukocidin (PVL) and γ-haemolysin CB (HlgCB) target human phagocytes. Binding of the toxins' S-components to human complement C5a receptor 1 (C5aR1) contributes to cellular tropism and human specificity of PVL and HlgCB. To investigate the role of both leukocidins during infection, we developed a human C5aR1 knock-in (hC5aR1 KI ) mouse model. HlgCB, but unexpectedly not PVL, contributed to increased bacterial loads in tissues of hC5aR1 KI mice. Compared to humans, murine hC5aR1 KI neutrophils showed a reduced sensitivity to PVL, which was mediated by the toxin's F-component LukF-PV. By performing a genome-wide CRISPR-Cas9 screen, we identified CD45 as a receptor for LukF-PV. The human-specific interaction between LukF-PV and CD45 provides a molecular explanation for resistance of hC5aR1 KI mouse neutrophils to PVL and probably contributes to the lack of a PVL-mediated phenotype during infection in these mice. This study demonstrates an unsuspected role of the F-component in driving the sensitivity of human phagocytes to PVL.

AB - The staphylococcal bi-component leukocidins Panton-Valentine leukocidin (PVL) and γ-haemolysin CB (HlgCB) target human phagocytes. Binding of the toxins' S-components to human complement C5a receptor 1 (C5aR1) contributes to cellular tropism and human specificity of PVL and HlgCB. To investigate the role of both leukocidins during infection, we developed a human C5aR1 knock-in (hC5aR1 KI ) mouse model. HlgCB, but unexpectedly not PVL, contributed to increased bacterial loads in tissues of hC5aR1 KI mice. Compared to humans, murine hC5aR1 KI neutrophils showed a reduced sensitivity to PVL, which was mediated by the toxin's F-component LukF-PV. By performing a genome-wide CRISPR-Cas9 screen, we identified CD45 as a receptor for LukF-PV. The human-specific interaction between LukF-PV and CD45 provides a molecular explanation for resistance of hC5aR1 KI mouse neutrophils to PVL and probably contributes to the lack of a PVL-mediated phenotype during infection in these mice. This study demonstrates an unsuspected role of the F-component in driving the sensitivity of human phagocytes to PVL.

UR - https://www.scopus.com/pages/publications/85046543245

U2 - 10.1038/s41564-018-0159-x

DO - 10.1038/s41564-018-0159-x

M3 - Article

C2 - 29736038

AN - SCOPUS:85046543245

SN - 2058-5276

VL - 3

SP - 708

EP - 717

JO - Nature Microbiology

JF - Nature Microbiology

IS - 6

ER -

Human CD45 is an f-component-specific receptor for the staphylococcal toxin Panton-Valentine leukocidin

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