The transcriptome of a complete episode of acute otitis media (original) (raw)
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American journal of rhinology & allergy, 2016
Acute otitis media (AOM) causes an inflammatory response in the middle ear. We assessed differences in innate immune responses involved in bacterial defense at onset of AOM in children who were stringently defined as otitis prone (sOP) and children not otitis prone (NOP). Innate immune genes analysis from middle ear fluid (MEF) samples of children. Genes of toll-like receptors (TLR), nod-like and retinoic acid-inducible gene-I-like receptors, downstream effectors important for inflammation and apoptosis, including cytokines and chemokines, were studied from MEF samples by using a real-time polymerase chain reaction array. Protein levels of differentially regulated genes were measured by Luminex. Gene expression in MEF among children who were sOP was significantly different in upregulation of interleukin 8, secretory leukocyte peptidase inhibitor, and chemokine (C-C motif) ligand 3, and in downregulation of interferon regulatory factor 7 and its related signaling molecules interferon...
Innate Signaling in Otitis Media: Pathogenesis and Recovery
Otitis media (OM) is the most prevalent childhood disease in developed countries. Involvement of innate immunity mediated by Toll-like receptors (TLRs) in OM has been implicated primarily in cell lines and by association studies of innate immune gene polymorphisms with OM prevalence. However, the precise role of innate immunity in OM is incompletely understood. We review recent research that has advanced our understanding of how innate immunity in the middle ear is mediated by the interaction of pathogen molecules with receptors such as the TLRs, leading to the activation of adaptor molecules and production of proinflammatory cytokines. TLR genes and signaling molecules are upregulated in OM in a murine model. Deletion of several key innate immune genes results in persistent OM in mice, coupled with an inability to clear bacterial infection from the middle ear. It is concluded that an intact innate immune signaling system is critical to recovery from bacterial OM.
International Immunology, 2013
Non-typeable Haemophilus influenzae (NTHi) causes acute otitis media (AOM) in young children. In our recent paper in Microbes and Infection we described the transcriptome signature elicited from PBMCs at onset of AOM caused by Streptococcus pneumoniae. In the current study we found very different results with NTHi AOM infections; 5.1% of 29 187 genes were differentially regulated by more than 2-fold at the onset of AOM compared with the pre-infection healthy state in the same children. Among the 1487 transcripts, 100 genes associated with the immune defense response were specifically analyzed. About half of the differentially regulated genes associated with antibacterial activity and the cell-mediated immune response were activated and half were suppressed. The important signatures for NTHi in children suggested that the balance of the immune response was toward suppression. Moreover, 90% of the genes associated with a pro-inflammatory cytokine response were down-regulated. The genes associated with the classic complement pathway were down-regulated, although the alternative complement pathway genes were up-regulated. These results provide the first human transcriptome data identifying gene expression in the immune response to be predominantly down-regulated at the onset of AOM due to NTHi.
Otolaryngology -- Head and Neck Surgery, 2013
Background. Otitis media (OM) is the most common childhood bacterial infection and also the leading cause of conductive hearing loss in children. Currently, there is an urgent need for developing novel therapeutic agents for treating OM based on full understanding of molecular pathogenesis in the areas of molecular biology, biochemistry, genetics, and animal model studies in OM.
Role of innate immunity in the pathogenesis of otitis media
International Journal of Infectious Diseases, 2014
Otitis media (OM) is one of the most frequent diseases afflicting humans and is prevalent in both developed and developing countries. 1 It represents a significant healthcare burden, with over 5 billion dollars spent every year in the world on this disease. 2 The term 'otitis media' covers a wide spectrum of disease, and is used to describe illnesses with predominantly middle ear symptoms. With its diverse clinical syndromes and affected host groups, OM remains one of the challenging diseases encountered in clinical practice. 3 It is the leading cause of hearing loss and is associated with significant morbidity. 4-7 Children are at greater risk and suffer most frequently from OM. This can cause serious deterioration in the quality of life. 8 Studies show that 80% of children will have experienced at least one episode of OM by their third birthday and 40% will have six or more recurrences by the age of 7 years. 9 OM is also the predominant reason for antibiotic prescription. 10 It is the primary indication for tympanostomy tube insertion, which is the most commonly performed operation on children. 11 The pathogenesis of OM is thought to be multifactorial and includes Eustachian tube dysfunction, allergy, viral and bacterial invasion, reduced ciliary function of both the middle ear and Eustachian tube mucosa, smoke exposure, gastro-esophageal reflux, and autoimmune and many other etiologies not yet fully understood. 12 OM can lead to life-threatening extracranial and intracranial complications. 13 Every year 28,000 deaths are attributable to OM complications, mainly through meningitis and brain abscess. 14,15 There are two main entities of OM: acute otitis media (AOM) and chronic suppurative otitis media (CSOM). 16 AOM is defined as the presence of inflammation in the middle ear accompanied by the rapid onset of signs and symptoms of an ear infection. Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are the most common causative agents of AOM. Despite antibiotic therapy, AOM can progress to CSOM, characterized by the persistent infection and inflammation of the middle ear and mastoid air cells. This condition typically involves a perforation of the tympanic membrane, with intermittent or continuous otorrhea. 17 As chronic otomastoiditis and
Nature communications, 2016
Acute otitis media (AOM) is among the most common pediatric diseases, and the most frequent reason for antibiotic treatment in children. Risk of AOM is dependent on environmental and host factors, as well as a significant genetic component. We identify genome-wide significance at a locus on 6q25.3 (rs2932989, Pmeta=2.15 × 10(-09)), and show that the associated variants are correlated with the methylation status of the FNDC1 gene (cg05678571, P=1.43 × 10(-06)), and further show it is an eQTL for FNDC1 (P=9.3 × 10(-05)). The mouse homologue, Fndc1, is expressed in middle ear tissue and its expression is upregulated upon lipopolysaccharide treatment. In this first GWAS of AOM and the largest OM genetic study to date, we identify the first genome-wide significant locus associated with AOM.
The Laryngoscope, 2015
Acute otitis media (AOM) is a common bacterial infection in childhood that causes an inflammatory response in the middle ear. Leukocytes produce different inflammatory molecules in vitro when stimulated with Gram-positive and Gram-negative bacteria. The major causes of AOM are Streptococcus pneumoniae, nontypeable Haemophilus influenza, and Moraxella catarrhalis. We sought to assess differences in cytokines, chemokines, and expression of Toll-like receptors (TLRs) at onset of AOM based on bacterial culture results. Middle ear fluid (MEF) from 66 children with AOM was studied. Innate immune genes, cytokines (interleukin [IL]-6, IL-8, IL-10, IL1-β; tumor necrosis factor-α), chemokines (CCL2, CCL3, CCL4, CCR5, CXCR3), and Toll-like receptors (TLR2, TLR4, TLR9) expression was measured using real-time reverse transcriptase-polymerase chain reaction (RT-PCR) from MEF collected in vivo by tympanocentesis. Culture-positive MEF had higher levels of all cytokines and chemokines (9-300-fold) a...
PloS one, 2014
Otitis media is one of the most common pediatric infections. While it is usually treated without difficulty, up to 20% of children may progress to long-term complications that include hearing loss, impaired speech and language development, academic underachievement, and irreversible disease. Hyperplasia of middle ear mucosa contributes to the sequelae of acute otitis media and is of important clinical significance. Understanding the role of growth factors in the mediation of mucosal hyperplasia could lead to the development of new therapeutic interventions for this disease and its sequelae. From a whole genome gene array analysis of mRNA expression during acute otitis media, we identified growth factors with expression kinetics temporally related to hyperplasia. We then tested these factors for their ability to stimulate mucosal epithelial growth in vitro, and determined protein levels and histological distribution in vivo for active factors. From the gene array, we identified seven...
Chronic suppurative otitis media causes macrophage-associated sensorineural hearing loss
Journal of Neuroinflammation
Background Chronic suppurative otitis media (CSOM) is the most common cause of permanent hearing loss in children in the developing world. A large component of the permanent hearing loss is sensory in nature and our understanding of the mechanism of this has so far been limited to post-mortem human specimens or acute infection models that are not representative of human CSOM. In this report, we assess cochlear injury in a validated Pseudomonas aeruginosa (PA) CSOM mouse model. Methods We generated persisters (PCs) and inoculated them into the mouse middle ear cavity. We tracked infection with IVIS and detected PA using RT-PCR. We assessed cochlear damage and innate immunity by Immunohistochemistry. Finally, we evaluated cytokines with multiplex assay and quantitative real-time PCR. Results We observed outer hair cell (OHC) loss predominantly in the basal turn of the cochlear at 14 days after bacterial inoculation. Macrophages, not neutrophils are the major immune cells in the cochle...
Proteomic Study Identifies Glycolytic and Inflammation Pathways Involved in Recurrent Otitis Media
International Journal of Molecular Sciences, 2020
Recurrent acute otitis media (RAOM) in children is clinically defined as the occurrence of at least three episodes of acute otitis media over a course of 6 months. A further common pathological condition of interest in the context of pediatric otolaryngology is adenotonsillar hypertrophy (ATH), a common cause of obstructive sleep apnea syndrome. Aimed at unraveling the differential modulation of proteins in the two pathologies and at understanding the possible pathways involved in their onset, we analyzed the proteomic profile of the adenoids from 14 RAOM and ATH patients by using two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS). The 2-DE coupled with MS allowed us to identify 23 spots with significant (p-value < 0.05) changes in protein amount, recognizing proteins involved in neutrophil degranulation and glycolysis pathways.