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

Publication Type:

Journal Article

Authors:

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

Source:

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

Keywords:

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

Abstract:

<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>

PDB: 
Epx1 (PDB ID: 7T4E) and Epx4 (PDB ID: 7T4D)
Detector: 
PILATUS
Beamline: 
24-ID-C
24-ID-E