Acute infection of mice with Clostridium difficile leads to eIF2α phosphorylation and pro‐survival signalling as part of the mucosal inflammatory response

Amir A Sadighi Akha; Casey M Theriot; John R Erb‐Downward; Andrew J McDermott; Nicole R Falkowski; Heather M Tyra; D. Thomas Rutkowski; Vincent B Young; Gary B Huffnagle

doi:10.1111/imm.12122

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Acute infection of mice with Clostridium difficile leads to eIF2α phosphorylation and pro‐survival signalling as part of the mucosal inflammatory response

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Acute infection of mice with Clostridium difficile leads to eIF2α phosphorylation and pro‐survival signalling as part of the mucosal inflammatory response

Amir A Sadighi Akha, Casey M Theriot, John R Erb‐Downward, Andrew J McDermott, Nicole R Falkowski, Heather M Tyra, D. Thomas Rutkowski, Vincent B Young and Gary B Huffnagle

Immunology, Vol.140(1), pp.111-122

09/2013

DOI: 10.1111/imm.12122

PMCID: PMC3809711

PMID: 23668260

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Abstract

Summary The current study sought to delineate the gene expression profile of the host response in the caecum and colon during acute infection with Clostridium difficile in a mouse model of infection, and to investigate the nature of the unfolded protein response in this process. The infected mice displayed a significant up‐regulation in the expression of chemokines (Cxcl1, Cxcl2 and Ccl2), numerous pro‐inflammatory cytokines (Ifng, Il1b, Il6, and Il17f), as well as Il22 and a number of anti‐microbial peptides (Defa1, Defa28, Defb1, Slpi and Reg3g) at the site(s) of infection. This was accompanied by a significant influx of neutrophils, dendritic cells, cells of the monocyte/macrophage lineage and all major subsets of lymphocytes to these site(s). However, CD4 T cells of the untreated and C. difficile‐infected mice expressed similar levels of CD69 and CD25. Neither tissue had up‐regulated levels of Tbx21, Gata3 or Rorc. The caeca and colons of the infected mice showed a significant increase in eukaryotic initiation factor 2α (eIF2α) phosphorylation, but neither the splicing of Xbp1 nor the up‐regulation of endoplasmic reticulum chaperones, casting doubt on the full‐fledged induction of the unfolded protein response by C. difficile. They also displayed significantly higher phosphorylation of AKT and signal transducer and activator of transcription 3 (STAT3), an indication of pro‐survival signalling. These data underscore the local, innate, pro‐inflammatory nature of the response to C. difficile and highlight eIF2α phosphorylation and the interleukin‐22–pSTAT3–RegIIIγ axis as two of the pathways that could be used to contain and counteract the damage inflicted on the intestinal epithelium.

eIF2α

pSTAT3

RegIIIγ

interleukin‐22

Clostridium difficile

Details

Title: Subtitle: Acute infection of mice with Clostridium difficile leads to eIF2α phosphorylation and pro‐survival signalling as part of the mucosal inflammatory response
Creators: Amir A Sadighi Akha - University of Michigan Medical School
Casey M Theriot - University of Michigan Medical School
John R Erb‐Downward - University of Michigan Medical School
Andrew J McDermott - University of Michigan Medical School
Nicole R Falkowski - University of Michigan Medical School
Heather M Tyra - University of Iowa
D. Thomas Rutkowski - University of Iowa
Vincent B Young - University of Michigan Medical School
Gary B Huffnagle - University of Michigan Medical School
Resource Type: Journal article
Publication Details: Immunology, Vol.140(1), pp.111-122
DOI: 10.1111/imm.12122
PMID: 23668260
PMCID: PMC3809711
NLM abbreviation: Immunology
ISSN: 0019-2805
eISSN: 1365-2567
Number of pages: 12
Language: English
Date published: 09/2013
Academic Unit: Anatomy and Cell Biology; Internal Medicine
Record Identifier: 9984094343502771

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