title: The transcriptome of a complete episode of acute otitis media.
abstract: BACKGROUND
  Otitis media is the most common disease of childhood, and represents an important health challenge to the 10-15% of children who experience chronic/recurrent middle ear infections. The middle ear undergoes extensive modifications during otitis media, potentially involving changes in the expression of many genes. Expression profiling offers an opportunity to discover novel genes and pathways involved in this common childhood disease. The middle ears of 320 WBxB6 F1 hybrid mice were inoculated with non-typeable Haemophilus influenzae (NTHi) or PBS (sham control). Two independent samples were generated for each time point and condition, from initiation of infection to resolution. RNA was profiled on Affymetrix mouse 430 2.0 whole-genome microarrays.
  
  
  RESULTS
  Approximately 8% of the sampled transcripts defined the signature of acute NTHi-induced otitis media across time. Hierarchical clustering of signal intensities revealed several temporal gene clusters. Network and pathway enrichment analysis of these clusters identified sets of genes involved in activation of the innate immune response, negative regulation of immune response, changes in epithelial and stromal cell markers, and the recruitment/function of neutrophils and macrophages. We also identified key transcriptional regulators related to events in otitis media, which likely determine the expression of these gene clusters. A list of otitis media susceptibility genes, derived from genome-wide association and candidate gene studies, was significantly enriched during the early induction phase and the middle re-modeling phase of otitis but not in the resolution phase. Our results further indicate that positive versus negative regulation of inflammatory processes occur with highly similar kinetics during otitis media, underscoring the importance of anti-inflammatory responses in controlling pathogenesis.
  
  
  CONCLUSIONS
  The results characterize the global gene response during otitis media and identify key signaling and transcription factor networks that control the defense of the middle ear against infection. These networks deserve further attention, as dysregulated immune defense and inflammatory responses may contribute to recurrent or chronic otitis in children.
authors.affiliation: Divisions of Surgery / Otolaryngology, University of California, San Diego, La Jolla, CA, USA. michelle_hernandez@med.unc.edu.|Department of Pediatrics, Division of Allergy, Immunology, Rheumatology, and Infectious Diseases, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. michelle_hernandez@med.unc.edu.
authors.forename: Michelle
authors.initials: M
authors.lastname: Hernandez
authors.affiliation: Divisions of Surgery / Otolaryngology, University of California, San Diego, La Jolla, CA, USA. ankeleichtle@yahoo.de.|Department of Otolaryngology, University of Lübeck, Lübeck, Germany. ankeleichtle@yahoo.de.
authors.forename: Anke
authors.initials: A
authors.lastname: Leichtle
authors.affiliation: Divisions of Surgery / Otolaryngology, University of California, San Diego, La Jolla, CA, USA. kpak@ucsd.edu.|VA San Diego Healthcare System, San Diego, CA, USA. kpak@ucsd.edu.
authors.forename: Kwang
authors.initials: K
authors.lastname: Pak
authors.affiliation: Medicine / Endocrinology, University of California, San Diego, La Jolla, CA, USA. nwebster@ucsd.edu.|VA San Diego Healthcare System, San Diego, CA, USA. nwebster@ucsd.edu.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Webster
authors.affiliation: Rheumatology, Allergy and Immunology, University of California, San Diego, La Jolla, CA, USA. swasserman@ucsd.edu.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Wasserman
authors.affiliation: Divisions of Surgery / Otolaryngology, University of California, San Diego, La Jolla, CA, USA. afryan@ucsd.edu.|VA San Diego Healthcare System, San Diego, CA, USA. afryan@ucsd.edu.
authors.forename: Allen F
authors.initials: AF
authors.lastname: Ryan
mesh_terms: D000208:Acute Disease; D000818:Animals; D004195:Disease Models, Animal; D004432:Ear, Middle / Q000378:metabolism*; D006192:Haemophilus Infections / Q000235:genetics* / Q000276:immunology; D006193:Haemophilus influenzae; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D010033:Otitis Media / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D059467:Transcriptome