Staphylococcus aureus (S. aureus) plays a predominant role in both hospital- and community-acquired infections [1]. Epidemiological studies have reported strong association of S. aureus strains causing necrotizing pneumonia and the presence of the bicomponent pore-forming toxin, Panton-Valentine leucocidin (PVL) [2, 3]. The role of PVL in S. aureus infections, however, remains controversial as PVL only kills human but not mouse cells [4]. There are increasing evidence that S. aureus use PVL to hijack host molecular pathway, and therefore, we used genome-wide CRISPR screen to identify novel host factors important for PVL-mediated cell death. The gene that was prioritised to be validated was FBXO11, which encodes member of F-box protein family. FBXO11 forms a part of E3-ubiquitin ligase complex SCF and is best known for its ability to suppress tumour [5]. Ablation of FBXO11 in human THP-1 macrophages using CRISPR/Cas9 resulted in decreased susceptibility to PVL, with clones showing <50% cell cytoxicity even at a concentration of 1mg/mL. Notably, our data indicate that, this decreased susceptibility may be associated with decrease in immune recognition of the toxin, rather than the disruption of cell death signalling. Surface level expression of C5aR1, a known PVL receptor, was investigated using western blot, flow cytometry and indirect immunofluorescence assay. It was shown that FBXO11 knockout cell lines have decreased expression of C5aR1 on the cell surface, and thereby decreased ability to bind the toxins. Here we propose a novel role for FBXO11 in regulating C5aR1 level in human THP-1 macrophages, thereby reducing its susceptibility to PVL.