PMID- 35259335
OWN - NLM
STAT- MEDLINE
DCOM- 20220418
LR  - 20240214
IS  - 1097-4172 (Electronic)
IS  - 0092-8674 (Print)
IS  - 0092-8674 (Linking)
VI  - 185
IP  - 7
DP  - 2022 Mar 31
TI  - Emerging enterococcus pore-forming toxins with MHC/HLA-I as receptors.
PG  - 1157-1171.e22
LID - S0092-8674(22)00142-8 [pii]
LID - 10.1016/j.cell.2022.02.002 [doi]
AB  - 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 beta-barrel 
      pore-forming toxins with a beta-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.
CI  - Copyright (c) 2022 Elsevier Inc. All rights reserved.
FAU - Xiong, Xiaozhe
AU  - Xiong X
AD  - 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.
FAU - Tian, Songhai
AU  - Tian S
AD  - 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.
FAU - Yang, Pan
AU  - Yang P
AD  - Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
FAU - Lebreton, Francois
AU  - Lebreton F
AD  - 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.
FAU - Bao, Huan
AU  - Bao H
AD  - Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 
      33458, USA.
FAU - Sheng, Kuanwei
AU  - Sheng K
AD  - Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, 
      MA 02115.
FAU - Yin, Linxiang
AU  - Yin L
AD  - 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.
FAU - Chen, Pengsheng
AU  - Chen P
AD  - 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.
FAU - Zhang, Jie
AU  - Zhang J
AD  - Department of Urology, Boston Children's Hospital, Department of Surgery, Harvard 
      Medical School, Boston, MA 02115, USA.
FAU - Qi, Wanshu
AU  - Qi W
AD  - Division of Endocrinology, Boston Children's Hospital, and Department of 
      Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
FAU - Ruan, Jianbin
AU  - Ruan J
AD  - 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.
FAU - Wu, Hao
AU  - Wu H
AD  - Vascular Biology Program, Department of Surgery, Boston Children's Hospital and 
      Harvard Medical School, Boston, MA 02115, USA.
FAU - Chen, Hong
AU  - Chen H
AD  - Vascular Biology Program, Department of Surgery, Boston Children's Hospital and 
      Harvard Medical School, Boston, MA 02115, USA.
FAU - Breault, David T
AU  - Breault DT
AD  - 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.
FAU - Wu, Hao
AU  - Wu H
AD  - 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.
FAU - Earl, Ashlee M
AU  - Earl AM
AD  - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
FAU - Gilmore, Michael S
AU  - Gilmore MS
AD  - 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.
FAU - Abraham, Jonathan
AU  - Abraham J
AD  - 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.
FAU - Dong, Min
AU  - Dong M
AD  - 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.
LA  - eng
GR  - S10 RR029205/RR/NCRR NIH HHS/United States
GR  - R21 NS106159/NS/NINDS NIH HHS/United States
GR  - HHSN272200900018C/AI/NIAID NIH HHS/United States
GR  - R01 NS080833/NS/NINDS NIH HHS/United States
GR  - DP2 GM140920/GM/NIGMS NIH HHS/United States
GR  - R01 HL093242/HL/NHLBI NIH HHS/United States
GR  - R01 AI132387/AI/NIAID NIH HHS/United States
GR  - R01 HL156362/HL/NHLBI NIH HHS/United States
GR  - R01 AI139087/AI/NIAID NIH HHS/United States
GR  - R01 NS117626/NS/NINDS NIH HHS/United States
GR  - P30 GM124165/GM/NIGMS NIH HHS/United States
GR  - P01 AI083214/AI/NIAID NIH HHS/United States
GR  - R01 HL130845/HL/NHLBI NIH HHS/United States
GR  - R01 EB021908/EB/NIBIB NIH HHS/United States
GR  - U19 AI110818/AI/NIAID NIH HHS/United States
GR  - P30 HD018655/HD/NICHD NIH HHS/United States
GR  - P30 DK034854/DK/NIDDK NIH HHS/United States
GR  - T32 HL007917/HL/NHLBI NIH HHS/United States
GR  - R01 HL137229/HL/NHLBI NIH HHS/United States
GR  - R01 AI158503/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20220307
PL  - United States
TA  - Cell
JT  - Cell
JID - 0413066
RN  - 0 (Bacterial Toxins)
RN  - 0 (Virulence Factors)
SB  - IM
CIN - Nat Rev Microbiol. 2022 May;20(5):253. PMID: 35314807
MH  - Animals
MH  - Bacterial Toxins/*metabolism
MH  - Cattle
MH  - *Enterococcus/metabolism/pathogenicity
MH  - Horses
MH  - *Leukocytes, Mononuclear
MH  - Mice
MH  - Microbial Sensitivity Tests
MH  - Swine
MH  - Virulence Factors/*metabolism
PMC - PMC8978092
MID - NIHMS1777956
OTO - NOTNLM
OT  - CRISPR screen
OT  - E. faecalis
OT  - E. faecium
OT  - E. hirae
OT  - Enterococcus
OT  - HLA-I
OT  - MHC-I
OT  - bacterial toxin
OT  - interferon
OT  - pore-forming toxin
COIS- Declaration of interests H.W. is on the advisory board of Cell. Boston Children's 
      Hospital has filed a provisional patent application on applications of Epxs 
      described here, with X.X, S.T., and M.D. as co-inventors. The other authors 
      declare no competing interests.
EDAT- 2022/03/09 06:00
MHDA- 2022/04/19 06:00
PMCR- 2023/03/31
CRDT- 2022/03/08 20:09
PHST- 2021/07/02 00:00 [received]
PHST- 2021/12/15 00:00 [revised]
PHST- 2022/02/01 00:00 [accepted]
PHST- 2022/03/09 06:00 [pubmed]
PHST- 2022/04/19 06:00 [medline]
PHST- 2022/03/08 20:09 [entrez]
PHST- 2023/03/31 00:00 [pmc-release]
AID - S0092-8674(22)00142-8 [pii]
AID - 10.1016/j.cell.2022.02.002 [doi]
PST - ppublish
SO  - Cell. 2022 Mar 31;185(7):1157-1171.e22. doi: 10.1016/j.cell.2022.02.002. Epub 
      2022 Mar 7.