Exploiting species specificity to understand the tropism of a human-specific toxin

Sci Adv. 2020 Mar 11;6(11):eaax7515. doi: 10.1126/sciadv.aax7515. eCollection 2020 Mar.


Many pathogens produce virulence factors that are specific toward their natural host. Clinically relevant methicillin-resistant Staphylococcus aureus (MRSA) isolates are highly adapted to humans and produce an array of human-specific virulence factors. One such factor is LukAB, a recently identified pore-forming toxin that targets human phagocytes by binding to the integrin component CD11b. LukAB exhibits strong tropism toward human, but not murine, CD11b. Here, phylogenetics and biochemical studies lead to the identification of an 11-residue domain required for the specificity of LukAB toward human CD11b, which is sufficient to render murine CD11b compatible with toxin binding. CRISPR-mediated gene editing was used to replace this domain, resulting in a "humanized" mouse. In vivo studies revealed that the humanized mice exhibit enhanced susceptibility to MRSA bloodstream infection, a phenotype mediated by LukAB. Thus, these studies establish LukAB as an important toxin for MRSA bacteremia and describe a new mouse model to study MRSA pathobiology.

Publication types

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

MeSH terms

  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Bacterial Toxins / genetics
  • Bacterial Toxins / metabolism*
  • CD11b Antigen / genetics
  • CD11b Antigen / metabolism*
  • HL-60 Cells
  • Humans
  • Leukocidins / genetics
  • Leukocidins / metabolism*
  • Methicillin-Resistant Staphylococcus aureus / genetics
  • Methicillin-Resistant Staphylococcus aureus / metabolism*
  • Mice
  • Mice, Transgenic
  • Staphylococcal Infections / genetics
  • Staphylococcal Infections / metabolism*
  • Virulence Factors / genetics
  • Virulence Factors / metabolism*


  • Bacterial Proteins
  • Bacterial Toxins
  • CD11b Antigen
  • ITGAM protein, human
  • Leukocidins
  • Virulence Factors
  • leukocidin AB, Staphylococcus aureus