Genetic variation of staphylococcal LukAB toxin determines receptor tropism

Nat Microbiol. 2021 Jun;6(6):731-745. doi: 10.1038/s41564-021-00890-3. Epub 2021 Apr 19.


Staphylococcus aureus has evolved into diverse lineages, known as clonal complexes (CCs), which exhibit differences in the coding sequences of core virulence factors. Whether these alterations affect 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. Together, this work advances our understanding of an important S. aureus toxin and underscores the importance of considering genetic variation in characterizing virulence factors and understanding the tug of war between pathogens and the host.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Proteins / genetics*
  • Bacterial Proteins / metabolism*
  • CD11b Antigen / genetics
  • CD11b Antigen / metabolism
  • Genetic Variation
  • Humans
  • Ion Channels / genetics
  • Ion Channels / metabolism*
  • Leukocidins / genetics*
  • Leukocidins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Phagocytes / metabolism
  • Phagocytes / microbiology
  • Staphylococcal Infections / genetics
  • Staphylococcal Infections / metabolism*
  • Staphylococcal Infections / microbiology
  • Staphylococcus aureus / genetics
  • Staphylococcus aureus / metabolism*


  • Bacterial Proteins
  • CD11b Antigen
  • HVCN1 protein, human
  • Ion Channels
  • Leukocidins
  • leukocidin AB, Staphylococcus aureus