PMID- 34748367
OWN - NLM
STAT- MEDLINE
DCOM- 20220221
LR  - 20220221
IS  - 1098-5522 (Electronic)
IS  - 0019-9567 (Print)
IS  - 0019-9567 (Linking)
VI  - 90
IP  - 1
DP  - 2022 Jan 25
TI  - IRE1alpha-Driven Inflammation Promotes Clearance of Citrobacter rodentium Infection.
PG  - e0048121
LID - 10.1128/IAI.00481-21 [doi]
LID - e00481-21
AB  - Endoplasmic reticulum (ER) stress is intimately linked with inflammation in 
      response to pathogenic infections. ER stress occurs when cells experience a 
      buildup of misfolded or unfolded protein during times of perturbation, such as 
      infections, which facilitates the unfolded protein response (UPR). The UPR 
      involves multiple host pathways in an attempt to reestablish homeostasis, which 
      oftentimes leads to inflammation and cell death if unresolved. The UPR is 
      activated to help resolve some bacterial infections, and the IRE1alpha pathway is 
      especially critical in mediating inflammation. To understand the role of the 
      IRE1alpha pathway of the UPR during enteric bacterial infection, we employed 
      Citrobacter rodentium to study host-pathogen interactions in intestinal 
      epithelial cells and the murine gastrointestinal (GI) tract. C. rodentium is an 
      enteric mouse pathogen that is similar to the human pathogens enteropathogenic 
      and enterohemorrhagic Escherichia coli (EPEC and EHEC, respectively), for which 
      we have limited small-animal models. Here, we demonstrate that both C. rodentium 
      and EPEC induced the UPR in intestinal epithelial cells. UPR induction during C. 
      rodentium infection correlated with the onset of inflammation in bone 
      marrow-derived macrophages (BMDMs). Our previous work implicated IRE1alpha and NOD1/2 
      in ER stress-induced inflammation, which we observed were also required for 
      proinflammatory gene induction during C. rodentium infection. C. rodentium 
      induced IRE1alpha-dependent inflammation in mice, and inhibiting IRE1alpha led to a 
      dysregulated inflammatory response and delayed clearance of C. rodentium. This 
      study demonstrates that ER stress aids inflammation and clearance of C. rodentium 
      through a mechanism involving the IRE1alpha-NOD1/2 axis.
FAU - Sweet, Lydia A
AU  - Sweet LA
AD  - Department of Immunology and Microbiology, University of Colorado Anschutz 
      Medical Campus, Aurora, Colorado, USA.
FAU - Kuss-Duerkop, Sharon K
AU  - Kuss-Duerkop SK
AD  - Department of Immunology and Microbiology, University of Colorado Anschutz 
      Medical Campus, Aurora, Colorado, USA.
FAU - Keestra-Gounder, A Marijke
AU  - Keestra-Gounder AM
AUID- ORCID: 0000-0002-2231-652X
AD  - Department of Immunology and Microbiology, University of Colorado Anschutz 
      Medical Campus, Aurora, Colorado, USA.
LA  - eng
GR  - R21 AI154043/AI/NIAID NIH HHS/United States
GR  - R21 AI164154/AI/NIAID NIH HHS/United States
GR  - R21AI154043/HHS | NIH | National Institute of Allergy and Infectious Diseases 
      (NIAID)/
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20211108
PL  - United States
TA  - Infect Immun
JT  - Infection and immunity
JID - 0246127
RN  - 0 (Biomarkers)
RN  - 0 (Nod1 Signaling Adaptor Protein)
RN  - 0 (Nod1 protein, mouse)
RN  - 0 (Nod2 Signaling Adaptor Protein)
RN  - 0 (Nod2 protein, mouse)
RN  - EC 2.7.11.1 (Ern1 protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 3.1.- (Endoribonucleases)
SB  - IM
MH  - Animals
MH  - *Bacterial Load
MH  - Biomarkers
MH  - Citrobacter rodentium/*physiology
MH  - Endoplasmic Reticulum Stress
MH  - Endoribonucleases/genetics/*metabolism
MH  - Enterobacteriaceae Infections/immunology/*metabolism/*microbiology
MH  - Gene Expression
MH  - *Host-Pathogen Interactions/immunology
MH  - Mice
MH  - Nod1 Signaling Adaptor Protein/genetics/metabolism
MH  - Nod2 Signaling Adaptor Protein/genetics/metabolism
MH  - Protein Serine-Threonine Kinases/genetics/*metabolism
MH  - Signal Transduction
PMC - PMC8788755
OTO - NOTNLM
OT  - Citrobacter
OT  - Citrobacter rodentium
OT  - EPEC
OT  - ER stress
OT  - Escherichia
OT  - IRE1a
OT  - IRE1alpha
OT  - KIRA6
OT  - NOD1
OT  - NOD1/2
OT  - NOD2
OT  - innate immunity
EDAT- 2021/11/09 06:00
MHDA- 2022/02/22 06:00
PMCR- 2022/01/25
CRDT- 2021/11/08 17:13
PHST- 2021/11/09 06:00 [pubmed]
PHST- 2022/02/22 06:00 [medline]
PHST- 2021/11/08 17:13 [entrez]
PHST- 2022/01/25 00:00 [pmc-release]
AID - 00481-21 [pii]
AID - iai.00481-21 [pii]
AID - 10.1128/IAI.00481-21 [doi]
PST - ppublish
SO  - Infect Immun. 2022 Jan 25;90(1):e0048121. doi: 10.1128/IAI.00481-21. Epub 2021 
      Nov 8.