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Open AccessArticle

Host–Receptor Post-Translational Modifications Refine Staphylococcal Leukocidin Cytotoxicity

Department of Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
Department of Microbiology, University of Chicago, Chicago, IL 60637, USA
Department of Microbiology and Immunology, UCSF Diabetes Center, Keck Center for Noncoding RNA, University of California, San Francisco, San Francisco, CA 94143, USA
Medical Faculty, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA
Author to whom correspondence should be addressed.
Toxins 2020, 12(2), 106;
Received: 12 January 2020 / Revised: 2 February 2020 / Accepted: 5 February 2020 / Published: 6 February 2020
(This article belongs to the Special Issue Staphylococcus aureus Toxins: Promoter or Handicap during Infection)
Staphylococcal bi-component pore-forming toxins, also known as leukocidins, target and lyse human phagocytes in a receptor-dependent manner. S-components of the leukocidins Panton-Valentine leukocidin (PVL), γ-haemolysin AB (HlgAB) and CB (HlgCB), and leukocidin ED (LukED) specifically employ receptors that belong to the class of G-protein coupled receptors (GPCRs). Although these receptors share a common structural architecture, little is known about the conserved characteristics of the interaction between leukocidins and GPCRs. In this study, we investigated host cellular pathways contributing to susceptibility towards S. aureus leukocidin cytotoxicity. We performed a genome-wide CRISPR/Cas9 library screen for toxin-resistance in U937 cells sensitized to leukocidins by ectopic expression of different GPCRs. Our screen identifies post-translational modification (PTM) pathways involved in the sulfation and sialylation of the leukocidin-receptors. Subsequent validation experiments show differences in the impact of PTM moieties on leukocidin toxicity, highlighting an additional layer of refinement and divergence in the staphylococcal host-pathogen interface. Leukocidin receptors may serve as targets for anti-staphylococcal interventions and understanding toxin-receptor interactions will facilitate the development of innovative therapeutics. Variations in the genes encoding PTM pathways could provide insight into observed differences in susceptibility of humans to infections with S. aureus.
Keywords: Staphylococcus aureus; bi-component pore-forming toxins; leukocidins; receptors; G-protein coupled receptors; post-translational modifications Staphylococcus aureus; bi-component pore-forming toxins; leukocidins; receptors; G-protein coupled receptors; post-translational modifications
MDPI and ACS Style

Tromp, A.T.; Van Gent, M.; Jansen, J.P.; Scheepmaker, L.M.; Velthuizen, A.; De Haas, C.J.; Van Kessel, K.P.; Bardoel, B.W.; Boettcher, M.; McManus, M.T.; Van Strijp, J.A.; Lebbink, R.J.; Haas, P.-J.; Spaan, A.N. Host–Receptor Post-Translational Modifications Refine Staphylococcal Leukocidin Cytotoxicity. Toxins 2020, 12, 106.

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