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

被引：37

作者：

Xiong, Xiaozhe ^{[1
,2
]}

Tian, Songhai ^{[1
,2
]}

Yang, Pan ^{[2
]}

Lebreton, Francois ^{[2
,3
,4
,5
]}

Bao, Huan ^{[6
]}

Sheng, Kuanwei ^{[7
]}

Yin, Linxiang ^{[1
,2
]}

Chen, Pengsheng ^{[1
,2
]}

Zhang, Jie ^{[1
]}

Qi, Wanshu ^{[8
,9
]}

Ruan, Jianbin ^{[10
,11
,14
]}

Wu, Hao ^{[10
,11
,12
,13
]}

Chen, Hong ^{[12
,13
]}

Breault, David T. ^{[8
,9
,15
]}

Wu, Hao ^{[10
,11
,12
,13
]}

Earl, Ashlee M. ^{[4
]}

Gilmore, Michael S. ^{[2
,3
,4
]}

Abraham, Jonathan ^{[2
,4
,16
]}

Dong, Min ^{[1
,2
]}

机构：

[1] Harvard Med Sch, Boston Childrens Hosp, Dept Urol, Dept Surg, Boston, MA 02115 USA

[2] Harvard Med Sch, Dept Microbiol, Boston, MA 02115 USA

[3] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA

[4] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[5] Walter Reed Army Inst Res, Multidrug Resistant Organism Repository & Surveil, Silver Spring, MD 20910 USA

[6] Scripps Res Inst, Dept Mol Med, Jupiter, FL 33458 USA

[7] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA

[8] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA

[9] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA

[10] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA

[11] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[12] Boston Childrens Hosp, Dept Surg, Vasc Biol Program, Boston, MA 02115 USA

[13] Harvard Med Sch, Boston, MA 02115 USA

[14] Univ Connecticut, Hlth Sch Med, Dept Immunol, Farmington, CT 06030 USA

[15] Harvard Stem Cell Inst, Cambridge, MA 02138 USA

[16] Brigham & Womens Hosp, Dept Med, Div Infect Dis, Boston, MA 02115 USA

来源：

CELL | 2022年 / 185卷 / 07期

基金：

美国国家卫生研究院;

关键词：

MHC CLASS-I; CRYSTAL-STRUCTURE; ALPHA-HEMOLYSIN; REVEALS; INTERFERON; MOLECULE; ANTIGEN; PREDICTION; COMPONENT; MECHANISM;

D O I：

10.1016/j.cell.2022.02.002

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 0-barrel pore-forming toxins with a 0-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.

引用

页码：1157 / +

页数：38

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