2022 - Emerging enterococcus pore-forming toxins with MHC/HLA-I as receptors
Orbit Mini Publication in Cell (2022)
Xiong X., Songhai Tian S., Yang P., Lebreton F., Bao H.,Sheng K., Yin L., Chen P., Zhang J., Qi W., Ruan J., Wu H., Chen H., Breault D.T., Wu H., Earl A.M., Gilmore M.S., Abraham J., Dong M.
Orbit Mini Publication in Cell (2022) doi:10.1016/j.cell.2022.02.002
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.