Gene expression profiles of early pneumococcal otitis media in the rat

Objective: To define the gene expression patterns during the early phases of a bacterial middle ear infection in the rat model. Method: Using cDNA gene array technology, we profiled the mRNA expression of 1176 genes in a rat model of acute otitis media. We identified changes in gene expression two-fold or greater 12 and 48 h after bilateral ME inoculation with either tryptic soy broth (TSB) or Streptococcus pneumoniae in TSB. Results: Transcripts of cytokines and cell adhesion molecules were up-regulated by 12 h, but returned to placebo transcription levels by 48 h. Three of six stress-response genes, including inducible nitric oxide synthase, GADD45 and heat shock protein 27 (HSP27) were up-regulated by 12 h, with HSP27 transcription levels continuing to rise through 48 h. All assayed transcription factors were up-regulated by 12 h, but only c-fos and c-jun up-regulation persisted to the 48-h time point. Up-regulation of apoptosis-related genes, except for bcl-x, was not evident until 48 h. These gene expression patterns reflected an early proinflammatory response consisting of cytokines, cell adhesion and stress-response molecules at 12 h followed by an up-regulation of apoptosis-related genes at 48 h. Conclusion: Downstream targets of several transcription factors, up-regulated transiently at 12 h, control secondary effects of S. pneumoniae infection, including apoptosis of neutrophils and mucosal epithetial cells, bone proliferation and promotion of leukocyte differentiation. These observations lead to a greater understanding of the early events in the pathogenesis of an AOM episode and highlight therapeutic targets, which may play a roll in the sequelae of AOM. (c) 2005 Elsevier Ireland Ltd. All rights reserved.