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

Xiaozhe Xiong; Songhai Tian; Pan Yang; Francois Lebreton; Huan Bao; Kuanwei Sheng; Linxiang Yin; Pengsheng Chen; Jie Zhang; Wanshu Qi; Jianbin Ruan; Hao Wu; Hong Chen; David T Breault; Hao Wu; Ashlee M Earl; Michael S Gilmore; Jonathan Abraham; Min Dong

doi:10.1016/j.cell.2022.02.002

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

Cell. 2022 Mar 31;185(7):1157-1171.e22. doi: 10.1016/j.cell.2022.02.002. Epub 2022 Mar 7.

Authors

Xiaozhe Xiong¹, Songhai Tian¹, Pan Yang², Francois Lebreton³, Huan Bao⁴, Kuanwei Sheng⁵, Linxiang Yin¹, Pengsheng Chen¹, Jie Zhang⁶, Wanshu Qi⁷, Jianbin Ruan⁸, Hao Wu⁹, Hong Chen⁹, David T Breault¹⁰, Hao Wu¹¹, Ashlee M Earl¹², Michael S Gilmore¹³, Jonathan Abraham¹⁴, Min Dong¹⁵

Affiliations

¹ 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.
² Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
³ Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA; Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Multidrug-Resistant Organism Repository and Surveillance Network (MRSN), Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
⁴ Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458, USA.
⁵ Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115.
⁶ Department of Urology, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115, USA.
⁷ Division of Endocrinology, Boston Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
⁸ Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Immunology, University of Connecticut Health School of Medicine, Farmington, CT 06030, USA.
⁹ Vascular Biology Program, Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
¹⁰ Division of Endocrinology, Boston Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
¹¹ Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
¹² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹³ Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA; Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: michael_gilmore@meei.harvard.edu.
¹⁴ Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: jonathan_abraham@hms.harvard.edu.
¹⁵ 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. Electronic address: min.dong@childrens.harvard.edu.

Abstract

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.

Keywords: CRISPR screen; E. faecalis; E. faecium; E. hirae; Enterococcus; HLA-I; MHC-I; bacterial toxin; interferon; pore-forming toxin.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bacterial Toxins / metabolism*
Cattle
Enterococcus* / metabolism
Enterococcus* / pathogenicity
Horses
Leukocytes, Mononuclear*
Mice
Microbial Sensitivity Tests
Swine
Virulence Factors / metabolism*

Substances

Bacterial Toxins
Virulence Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding