Acute infection of mice with Clostridium difficile leads to eIF2 alpha phosphorylation and pro-survival signalling as part of the mucosal inflammatory response

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

来源：Immunology, 2013, 140(1): 111-122.

DOI：10.1111/imm.12122

• Clostridium difficile
• eIF2 alpha
• interleukin-22
• pSTAT3
• RegIII gamma

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 2 (eIF2) 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 eIF2 phosphorylation and the interleukin-22-pSTAT3-RegIII axis as two of the pathways that could be used to contain and counteract the damage inflicted on the intestinal epithelium.

• 出版日期2013-9