Xiong Xiaozhe, Tian Songhai, Yang Pan, Lebreton Francois, Bao Huan, Sheng Kuanwei, Yin Linxiang, Chen Pengsheng, Zhang Jie, Qi Wanshu, Ruan Jianbin, Wu Hao, Chen Hong, Breault David T, Wu Hao, Earl Ashlee M, Gilmore Michael S, Abraham Jonathan, Dong Min
Department of Urology, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
Cell. 2022 Mar 31;185(7):1157-1171.e22. doi: 10.1016/j.cell.2022.02.002. Epub 2022 Mar 7.
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.
肠球菌是人类微生物群的一部分，也是多重耐药感染的主要原因。在此，我们在全球分离的粪肠球菌、屎肠球菌和希氏肠球菌菌株中鉴定出一个肠球菌成孔毒素（Epxs）家族。结构研究表明，Epxs形成了β-桶形成孔毒素的一个分支，其β-桶突出部（称为顶部结构域）位于帽结构域之上。通过全基因组CRISPR-Cas9筛选，我们确定人类白细胞抗原I类（HLA-I）复合体是两个成员（Epx2和Epx3）的受体，这两个成员优先识别源自人类、马、牛和猪而非小鼠的HLA-I和同源MHC-I。干扰素暴露可刺激MHC-I表达，使人细胞和肠道类器官对Epx2和Epx3的毒性敏感。与携带Epx2的屎肠球菌共培养会损害人类外周血单核细胞和肠道类器官，且这种毒性可被Epx2抗体中和，证明携带Epx的肠球菌的毒素介导的毒力。
