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

Publication Type:

Journal Article


Cell, Volume 185, Issue 7, p.1157-1171.e22 (2022)


Animals, Anti-Bacterial Agents, Cattle, Enterococcus, Horses, Leukocytes, Mononuclear, Mice, Microbial Sensitivity Tests, Swine, Virulence Factors


<p>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.&nbsp;faecalis, E.&nbsp;faecium, and E.&nbsp;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.&nbsp;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.</p>

Epx1 (PDB ID: 7T4E) and Epx4 (PDB ID: 7T4D)