PMID- 30126899
OWN - NLM
STAT- MEDLINE
DCOM- 20190412
LR  - 20231101
IS  - 1098-5522 (Electronic)
IS  - 0019-9567 (Print)
IS  - 0019-9567 (Linking)
VI  - 86
IP  - 11
DP  - 2018 Nov
TI  - Molecular Determinants of Enterotoxigenic Escherichia coli Heat-Stable Toxin 
      Secretion and Delivery.
LID - 10.1128/IAI.00526-18 [doi]
LID - e00526-18
AB  - Enterotoxigenic Escherichia coli (ETEC), a heterogeneous diarrheal pathovar 
      defined by production of heat-labile (LT) and/or heat-stable (ST) toxins, causes 
      substantial morbidity among young children in the developing world. Studies 
      demonstrating a major burden of ST-producing ETEC have focused interest on ST 
      toxoids for ETEC vaccines. We examined fundamental aspects of ST biology using 
      ETEC strain H10407, which carries estH and estP genes encoding STh and STp, 
      respectively, in addition to eltAB genes responsible for LT. Here, we found that 
      deletion of estH significantly diminished cyclic GMP (cGMP) activation in target 
      epithelia, while deletion of estP had a surprisingly modest impact, and a dual 
      estH estP mutant was not appreciably different from the estH mutant. However, we 
      noted that either STh or STp recombinant peptides stimulated cGMP production and 
      that the loss of estP was compensated by enhanced estH transcription. We also 
      found that the TolC efflux protein was essential for toxin secretion and 
      delivery, providing a potential avenue for efflux inhibitors in treatment of 
      acute diarrheal illness. In addition, we demonstrated that the EtpA adhesin is 
      required for optimal delivery of ST and that antibodies against either the 
      adhesin or STh significantly impaired toxin delivery and cGMP activation in 
      target T84 cells. Finally, we used FLAG epitope fusions to demonstrate that the 
      STh propeptide sequence is secreted by ETEC, potentially providing additional 
      epitopes for antibody neutralization. These studies collectively extend our 
      understanding of ETEC pathogenesis and potentially inform additional avenues to 
      mitigate disease by these common diarrheal pathogens.
CI  - Copyright (c) 2018 American Society for Microbiology.
FAU - Zhu, Yuehui
AU  - Zhu Y
AD  - Division of Infectious Diseases, Department of Medicine, Washington University 
      School of Medicine, St. Louis, Missouri, USA.
FAU - Luo, Qingwei
AU  - Luo Q
AD  - Division of Infectious Diseases, Department of Medicine, Washington University 
      School of Medicine, St. Louis, Missouri, USA.
FAU - Davis, Sierra M
AU  - Davis SM
AD  - Division of Infectious Diseases, Department of Medicine, Washington University 
      School of Medicine, St. Louis, Missouri, USA.
FAU - Westra, Chase
AU  - Westra C
AD  - Division of Infectious Diseases, Department of Medicine, Washington University 
      School of Medicine, St. Louis, Missouri, USA.
FAU - Vickers, Tim J
AU  - Vickers TJ
AD  - Division of Infectious Diseases, Department of Medicine, Washington University 
      School of Medicine, St. Louis, Missouri, USA.
FAU - Fleckenstein, James M
AU  - Fleckenstein JM
AUID- ORCID: 0000-0002-1148-697X
AD  - Division of Infectious Diseases, Department of Medicine, Washington University 
      School of Medicine, St. Louis, Missouri, USA jflecken@wustl.edu.
AD  - Medicine Service, Department of Veterans Affairs Medical Center, St. Louis, 
      Missouri, USA.
LA  - eng
GR  - I01 BX001469/BX/BLRD VA/United States
GR  - R01 AI089894/AI/NIAID NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
GR  - R01 AI126887/AI/NIAID NIH HHS/United States
GR  - I01 BX004825/BX/BLRD VA/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 - 20181025
PL  - United States
TA  - Infect Immun
JT  - Infection and immunity
JID - 0246127
RN  - 0 (Bacterial Outer Membrane Proteins)
RN  - 0 (Bacterial Toxins)
RN  - 0 (Enterotoxins)
RN  - 0 (Escherichia coli Proteins)
RN  - 0 (Membrane Transport Proteins)
RN  - 0 (heat stable toxin (E coli))
RN  - 0 (tolC protein, E coli)
RN  - H2D2X058MU (Cyclic GMP)
SB  - IM
MH  - Bacterial Outer Membrane Proteins/metabolism
MH  - Bacterial Toxins/*genetics/*metabolism
MH  - Cell Line
MH  - Cyclic GMP/metabolism
MH  - Enterotoxigenic Escherichia coli/*genetics/*metabolism
MH  - Enterotoxins/*genetics/*metabolism
MH  - Epithelial Cells/microbiology/pathology
MH  - Escherichia coli Proteins/*genetics/*metabolism
MH  - Gene Deletion
MH  - Humans
MH  - Membrane Transport Proteins/metabolism
PMC - PMC6204697
OTO - NOTNLM
OT  - diarrhea
OT  - enterotoxigenic
OT  - heat-stable toxin
OT  - pathogenesis
OT  - toxoids
OT  - vaccines
EDAT- 2018/08/22 06:00
MHDA- 2019/04/13 06:00
PMCR- 2019/04/25
CRDT- 2018/08/22 06:00
PHST- 2018/07/06 00:00 [received]
PHST- 2018/08/15 00:00 [accepted]
PHST- 2018/08/22 06:00 [pubmed]
PHST- 2019/04/13 06:00 [medline]
PHST- 2018/08/22 06:00 [entrez]
PHST- 2019/04/25 00:00 [pmc-release]
AID - IAI.00526-18 [pii]
AID - 00526-18 [pii]
AID - 10.1128/IAI.00526-18 [doi]
PST - epublish
SO  - Infect Immun. 2018 Oct 25;86(11):e00526-18. doi: 10.1128/IAI.00526-18. Print 2018 
      Nov.