Emerging enterococcus pore-forming toxins with MHC/HLA-I as receptors

Cell. 2022 Mar 31;185(7):1157-1171.e22. doi: 10.1016/j.cell.2022.02.002. Epub 2022 Mar 7.

Abstract

Enterococci are a part of human microbiota and a leading cause of multidrug resistant infections. Here, we identify a family of Enterococcus pore-forming toxins (Epxs) in E. faecalis, E. faecium, and E. hirae strains isolated across the globe. Structural studies reveal that Epxs form a branch of β-barrel pore-forming toxins with a β-barrel protrusion (designated the top domain) sitting atop the cap domain. Through a genome-wide CRISPR-Cas9 screen, we identify human leukocyte antigen class I (HLA-I) complex as a receptor for two members (Epx2 and Epx3), which preferentially recognize human HLA-I and homologous MHC-I of equine, bovine, and porcine, but not murine, origin. Interferon exposure, which stimulates MHC-I expression, sensitizes human cells and intestinal organoids to Epx2 and Epx3 toxicity. Co-culture with Epx2-harboring E. faecium damages human peripheral blood mononuclear cells and intestinal organoids, and this toxicity is neutralized by an Epx2 antibody, demonstrating the toxin-mediated virulence of Epx-carrying Enterococcus.

Keywords: CRISPR screen; E. faecalis; E. faecium; E. hirae; Enterococcus; HLA-I; MHC-I; bacterial toxin; interferon; pore-forming toxin.

Publication types

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

MeSH terms

  • Animals
  • Bacterial Toxins / metabolism*
  • Cattle
  • Enterococcus* / metabolism
  • Enterococcus* / pathogenicity
  • Horses
  • Leukocytes, Mononuclear*
  • Mice
  • Microbial Sensitivity Tests
  • Swine
  • Virulence Factors / metabolism*

Substances

  • Bacterial Toxins
  • Virulence Factors