PMID- 24098122
OWN - NLM
STAT- MEDLINE
DCOM- 20140526
LR  - 20230217
IS  - 1553-7374 (Electronic)
IS  - 1553-7366 (Print)
IS  - 1553-7366 (Linking)
VI  - 9
IP  - 10
DP  - 2013
TI  - Ehrlichia chaffeensis uses its surface protein EtpE to bind GPI-anchored protein 
      DNase X and trigger entry into mammalian cells.
PG  - e1003666
LID - 10.1371/journal.ppat.1003666 [doi]
LID - e1003666
AB  - Ehrlichia chaffeensis, an obligatory intracellular rickettsial pathogen, enters 
      and replicates in monocytes/macrophages and several non-phagocytic cells. E. 
      chaffeensis entry into mammalian cells is essential not only for causing the 
      emerging zoonosis, human monocytic ehrlichiosis, but also for its survival. It 
      remains unclear if E. chaffeensis has evolved a specific surface protein that 
      functions as an 'invasin' to mediate its entry. We report a novel entry 
      triggering protein of Ehrlichia, EtpE that functions as an invasin. EtpE is an 
      outer membrane protein and an antibody against EtpE (the C-terminal fragment, 
      EtpE-C) greatly inhibited E. chaffeensis binding, entry and infection of both 
      phagocytes and non-phagocytes. EtpE-C-immunization of mice significantly 
      inhibited E. chaffeensis infection. EtpE-C-coated latex beads, used to 
      investigate whether EtpE-C can mediate cell invasion, entered both phagocytes and 
      non-phagocytes and the entry was blocked by compounds that block E. chaffeensis 
      entry. None of these compounds blocked uptake of non-coated beads by phagocytes. 
      Yeast two-hybrid screening revealed that DNase X, a glycosylphosphatidyl 
      inositol-anchored mammalian cell-surface protein binds EtpE-C. This was confirmed 
      by far-Western blotting, affinity pull-down, co-immunoprecipitation, 
      immunofluorescence labeling, and live-cell image analysis. EtpE-C-coated beads 
      entered bone marrow-derived macrophages (BMDMs) from wild-type mice, whereas they 
      neither bound nor entered BMDMs from DNase X(-/-) mice. Antibody against DNase X 
      or DNase X knock-down by small interfering RNA impaired E. chaffeensis binding, 
      entry, and infection. E. chaffeensis entry and infection rates of BMDMs from 
      DNase X(-/-) mice and bacterial load in the peripheral blood in experimentally 
      infected DNase X(-/-) mice, were significantly lower than those from wild-type 
      mice. Thus this obligatory intracellular pathogen evolved a unique protein EtpE 
      that binds DNase X to enter and infect eukaryotic cells. This study is the first 
      to demonstrate the invasin and its mammalian receptor, and their in vivo 
      relevance in any ehrlichial species.
FAU - Mohan Kumar, Dipu
AU  - Mohan Kumar D
AD  - Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio 
      State University, Columbus, Ohio, United States of America.
FAU - Yamaguchi, Mamoru
AU  - Yamaguchi M
FAU - Miura, Koshiro
AU  - Miura K
FAU - Lin, Mingqun
AU  - Lin M
FAU - Los, Marek
AU  - Los M
FAU - Coy, Johannes F
AU  - Coy JF
FAU - Rikihisa, Yasuko
AU  - Rikihisa Y
LA  - eng
GR  - R01AI30010/AI/NIAID NIH HHS/United States
GR  - R01 AI030010/AI/NIAID NIH HHS/United States
GR  - R01 AI047885/AI/NIAID NIH HHS/United States
GR  - R01 AI121124/AI/NIAID NIH HHS/United States
GR  - R01AI047885/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20131003
PL  - United States
TA  - PLoS Pathog
JT  - PLoS pathogens
JID - 101238921
RN  - 0 (Bacterial Outer Membrane Proteins)
RN  - 0 (GPI-Linked Proteins)
RN  - EC 3.1.- (Deoxyribonucleases)
SB  - IM
MH  - Animals
MH  - Bacterial Outer Membrane Proteins/genetics/*metabolism
MH  - Deoxyribonucleases/genetics/*metabolism
MH  - Dogs
MH  - Ehrlichia chaffeensis
MH  - Ehrlichiosis/genetics/*metabolism/pathology
MH  - GPI-Linked Proteins/*metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Mice
MH  - Mice, Knockout
MH  - Phagocytes/*metabolism/microbiology/pathology
MH  - Protein Binding
PMC - PMC3789761
COIS- JFC is employed by Vorstand/CSO TAVARLIN AG and has patent applications 
      (pending), including individual applications or those belonging to the 
      institution to which he is affiliated. This does not alter our adherence to all 
      PLOS Pathogens policies on sharing data and materials. All other authors have 
      declared that no competing interests exist.
EDAT- 2013/10/08 06:00
MHDA- 2014/05/27 06:00
PMCR- 2013/10/03
CRDT- 2013/10/08 06:00
PHST- 2013/03/27 00:00 [received]
PHST- 2013/08/12 00:00 [accepted]
PHST- 2013/10/08 06:00 [entrez]
PHST- 2013/10/08 06:00 [pubmed]
PHST- 2014/05/27 06:00 [medline]
PHST- 2013/10/03 00:00 [pmc-release]
AID - PPATHOGENS-D-13-00855 [pii]
AID - 10.1371/journal.ppat.1003666 [doi]
PST - ppublish
SO  - PLoS Pathog. 2013;9(10):e1003666. doi: 10.1371/journal.ppat.1003666. Epub 2013 
      Oct 3.