%0 Journal Article %J Cell %D 2022 %T Emerging enterococcus pore-forming toxins with MHC/HLA-I as receptors %A Xiong, Xiaozhe %A Tian, Songhai %A Pan Yang %A Lebreton, Francois %A Bao, Huan %A Sheng, Kuanwei %A Yin, Linxiang %A Chen, Pengsheng %A Zhang, Jie %A Qi, Wanshu %A Ruan, Jianbin %A Wu, Hao %A Chen, Hong %A Breault, David T %A Wu, Hao %A Earl, Ashlee M %A Gilmore, Michael S %A Jonathan Abraham %A Dong, Min %X 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. %B Cell %8 2022 Mar 02 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/35259335?dopt=Abstract %R 10.1016/j.cell.2022.02.002