title: Acute infection of mice with Clostridium difficile leads to eIF2α phosphorylation and pro-survival signalling as part of the mucosal inflammatory response.
abstract: 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.
authors.affiliation: Divisions of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-5642, USA.
authors.forename: Amir A
authors.initials: AA
authors.lastname: Sadighi Akha
authors.forename: Casey M
authors.initials: CM
authors.lastname: Theriot
authors.forename: John R
authors.initials: JR
authors.lastname: Erb-Downward
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McDermott
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Falkowski
authors.forename: Heather M
authors.initials: HM
authors.lastname: Tyra
authors.forename: D Thomas
authors.initials: DT
authors.lastname: Rutkowski
authors.forename: Vincent B
authors.initials: VB
authors.lastname: Young
authors.forename: Gary B
authors.initials: GB
authors.lastname: Huffnagle
mesh_terms: D000208:Acute Disease; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics; D018925:Chemokines / Q000235:genetics; D016360:Clostridioides difficile / Q000276:immunology / Q000472:pathogenicity; D016207:Cytokines / Q000235:genetics; D004761:Enterocolitis, Pseudomembranous / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D018836:Inflammation Mediators / Q000378:metabolism; D007378:Interleukins / Q000235:genetics; D007413:Intestinal Mucosa / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D015398:Signal Transduction; D059467:Transcriptome; D056811:Unfolded Protein Response; D000097043:Interleukin-22
chemical_list: D023181:Antimicrobial Cationic Peptides; D018925:Chemokines; D016207:Cytokines; D015852:Eukaryotic Initiation Factor-2; D018836:Inflammation Mediators; D007378:Interleukins; D000097043:Interleukin-22
keywords: Clostridium difficile; RegIIIγ; eIF2α; interleukin-22; pSTAT3