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.