Genetic variation of staphylococcal LukAB toxin determines receptor tropism

Staphylococcus aureus have evolved into diverse lineages, known as clonal complexes (“CC”), which exhibit differences in the coding sequences of core virulence factors. Whether these alterations impact functionality is poorly understood. Here, we studied the highly polymorphic pore-forming toxin LukAB. We discovered that the LukAB toxin variants produced by S. aureus CC30 and CC45 kill human phagocytes regardless of whether CD11b, the previously established LukAB receptor, is present, and instead target the human hydrogen voltage-gated channel 1 (HVCN1). Biochemical studies identified the domain within human HVCN1 that drives LukAB species specificity, enabling the generation of humanized HVCN1 mice with enhanced susceptibility to CC30 LukAB and to bloodstream infection caused by CC30 S. aureus strains. Altogether, this work advances our understanding of an important S. aureus toxin and underscores the importance of considering genetic variation to characterizing virulence factors and understand the tug of war between pathogens and the host.