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Toll-Like Receptors: Expression and Roles in Otitis Media.

ABSTRACT: Otitis media is mainly caused by upper respiratory tract infection and eustachian tube dysfunction. If external upper respiratory tract infection is not detected early in the middle ear, or an appropriate immune response does not occur, otitis media can become a chronic state or complications may occur. Therefore, given the important role of Toll-like receptors (TLRs) in the early response to external antigens, we surveyed the role of TLRs in otitis media. To summarize the role of TLR in otitis media, we reviewed articles on the expression of TLRs in acute otitis media (AOM), otitis media with effusion (OME), chronic otitis media (COM) with cholesteatoma, and COM without cholesteatoma. Many studies showed that TLRs 1-10 are expressed in AOM, OME, COM with cholesteatoma, and COM without cholesteatoma. TLR expression in the normal middle ear mucosa is absent or weak, but is increased in inflammatory fluid of AOM, effusion of OME, and granulation tissue and cholesteatoma of COM. In addition, TLRs show increased or decreased expression depending on the presence or absence of bacteria, recurrence of disease, tissue type, and repeated surgery. In conclusion, expression of TLRs is associated with otitis media. Inappropriate TLR expression, or delayed or absent induction, are associated with the occurrence, recurrence, chronicization, and complications of otitis media. Therefore, TLRs are very important in otitis media and closely related to its etiology.

SUBMITTER: Jung SY

PROVIDER: S-EPMC8346131 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The toll-Like receptor adaptor TRIF contributes to otitis media pathogenesis and recovery.

Project description:BackgroundToll-like receptor (TLR) signalling is crucial for innate immune responses to infection. The involvement of TLRs in otitis media (OM), the most prevalent childhood disease in developed countries, has been implicated by studies in middle ear cell lines, by association studies of TLR-related gene polymorphisms, and by altered OM in mice bearing mutations in TLR genes. Activated TLRs signal via two alternative intracellular signaling molecules with differing effects; MyD88 (Myeloid differentiation primary response gene 88) inducing primarily interleukin expression and TRIF (Tir-domain-containing adaptor inducing interferon beta) mediating type I interferon (IFN) expression. We tested the hypothesis that TRIF and type I IFN signaling play a role in OM, using a murine model of OM induced by non-typeable Haemophilus influenzae (NTHi). The ME inflammatory response to NTHi was examined in wild-type (WT) and TRIF-/- mice by qPCR, gene microarray, histopathology and bacterial culture.ResultsExpression of TRIF mRNA was only modesty enhanced during OM, but both type I IFN signalling genes and type I IFN-inducible genes were significantly up-regulated in WT mice. TRIF-deficient mice showed reduced but more persistent mucosal hyperplasia and less leukocyte infiltration into the ME in response to NTHi infection than did WT animals. Viable bacteria could be cultured from MEs of TRIF-/- mice for much longer in the course of disease than was the case for middle ears of WT mice.ConclusionOur results demonstrate that activation of TRIF/type I IFN responses is important in both the pathogenesis and resolution of NTHi-induced OM.

| S-EPMC2736931 | biostudies-literature

Otitis media metagenome

Project description:Impact of narrow-spectrum antibiotics on the oral and fecal microbiome and resistome in a young child treated for otitis media

| PRJEB31957 | ENA

Otitis Media Impact on Ear

Project description:This SuperSeries is composed of the SubSeries listed below.

2013-07-23 | GSE49129 | GEO

Expression of toll-like receptors and their regulatory roles in murine cardiac telocytes.

Project description:Telocytes, newly discovered in the last decade, are interstitial cells found in numerous organs, with multiple proposed potential biological functions. Toll-like receptors (TLRs) play an important role in innate and adaptive immunity by recognizing pathogen-associated molecular patterns (PAMPs). However, it is still unknown whether telocytes express these innate receptors. We sought to determine the expression and role of TLRs in telocytes. In our study, we primarily detected TLR1-9 expression in telocytes. The proliferation, apoptosis and immunoregulatory activity of telocytes activated with or without TLR ligands were determined. Our results showed that purified telocytes expressed TLR2, TLR3 and TLR5. In particular, telocytes expressed high levels of TLR2 as observed using flow cytometry. When we stimulated telocytes with TLR2 or TLR3 agonists (Pam3CSK4, PolyI:C), iNOS expression was greatly increased after Pam3CSK4 treatment. Additionally, telocyte proliferation was reduced and cell apoptosis was increased after TLR agonist stimulation. A co-culture experiment showed that supernatant from telocytes pretreated with Pam3CSK4 inhibited T cell activation much more than that from untreated telocytes and this effect was mediated by iNOS. Overall, our results demonstrated TLR expression on telocytes for the first time and provided evidence of an immunoregulatory role of telocytes, indicating their clinical potential.

| S-EPMC6653320 | biostudies-literature

Otitis Media Impact on Middle Ear

Project description:Objective: Otitis media is known to alter expression of cytokine and other genes in the mouse middle ear and inner ear. However, whole mouse genome studies of gene expression in otitis media have not previously been undertaken. Ninety-nine percent of mouse genes are shared in the human, so these studies are relevant to the human condition. Methods: To assess inflammation-driven processes in the mouse ear, gene chip analyses were conducted on mice treated with trans-tympanic heat-killed Hemophilus influenza using untreated mice as controls. Middle and inner ear tissues were separately harvested at 6 hours, RNA extracted, and samples for each treatment processed on the Affymetrix 430 2.0 Gene Chip for expression of its 34,000 genes. Results: Statistical analysis of gene expression compared to control mice showed significant alteration of gene expression in 2,355 genes, 11% of the genes tested and 8% of the mouse genome. Significant middle and inner ear upregulation (fold change >1.5, p<0.05) was seen in 1,081 and 599 genes respectively. Significant middle and inner ear downregulation (fold change <0.67, p<0.05) was seen in 978 and 287 genes respectively. While otitis media is widely believed to be an exclusively middle ear process with little impact on the inner ear, the inner ear changes noted in this study were numerous and discrete from the middle ear responses. This suggests that the inner ear does indeed respond to otitis media and that its response is a distinctive process. Numerous new genes, previously not studied, are found to be affected by inflammation in the ear. Conclusion: Whole genome analysis via gene chip allows simultaneous examination of expression of hundreds of gene families influenced by inflammation in the middle ear. Discovery of new gene families affected by inflammation may lead to new approaches to the study and treatment of otitis media.

2013-07-23 | GSE49128 | GEO

Otitis Media Impact on Inner Ear

2013-07-23 | GSE49122 | GEO

Acute Otitis Media Curriculum.

Project description:IntroductionStudies have shown that clinicians do a poor job of diagnosing middle ear infections, and an inaccurate diagnosis may result in inappropriate treatment, such as overuse of antibiotics. Antibiotic overuse is known to lead to increased bacterial resistance and puts patients at risk of deleterious side effects, including allergic reactions, vomiting, diarrhea, and rash. In this curriculum, we teach three important topics for achieving a successful middle ear exam and diagnosis of pathology.MethodsThe topics covered during the session are middle ear examination techniques, diagnosis of middle ear pathology and criteria for diagnosing acute otitis media, and treatment of acute otitis media. Each topic has a 30-minute lesson plan with broad goals, specific and measurable learning objectives, interactive learning activities, and assessment measures. Teaching activities include a mix of knowledge, skill, and attitude activities. Assessment measures aim at the highest level of Miller's pyramid of assessment when possible. Also included is a scholarship map that relates how this learning activity can fit into the assessment of learners at the program level by linking learning objectives with pediatric developmental milestones.ResultsThe interactive nature of these lessons has been very well received by learners, and pediatric residents have had a self-perceived increase in skills.DiscussionThis curriculum provides a standardized approach to teaching the middle ear exam structured by educational rubrics and allows for accurate assessment of learners.

| S-EPMC6440425 | biostudies-literature

Predisposition to Childhood Otitis Media and Genetic Polymorphisms within the Toll-Like Receptor 4 (TLR4) Locus.

Project description:Predisposition to childhood otitis media (OM) has a strong genetic component, with polymorphisms in innate immunity genes suspected to contribute to risk. Studies on several genes have been conducted, but most associations have failed to replicate in independent cohorts.We investigated 53 gene polymorphisms in a Finnish cohort of 624 cases and 778 controls. A positive association signal was followed up in a tagging approach and tested in an independent Finnish cohort of 205 cases, in a British cohort of 1269 trios, as well as in two cohorts from the United States (US); one with 403 families and the other with 100 cases and 104 controls.In the initial Finnish cohort, the SNP rs5030717 in the TLR4 gene region showed significant association (OR 1.33, P = .003) to OM. Tagging SNP analysis of the gene found rs1329060 (OR 1.33, P = .002) and rs1329057 (OR 1.29, P = .003) also to be associated. In the more severe phenotype the association was stronger. This finding was supported by an independent Finnish case cohort, but the associations failed to replicate in the British and US cohorts. In studies on TLR4 signaling in 20 study subjects, the three-marker risk haplotype correlated with a decreased TNF? secretion in myeloid dendritic cells.The TLR4 gene locus, regulating the innate immune response, influences the genetic predisposition to childhood OM in a subpopulation of patients. Environmental factors likely modulate the genetic components contributing to the risk of OM.

| S-EPMC4503307 | biostudies-literature

Influenza-induced inflammation drives pneumococcal otitis media

Project description:Influenza A virus (IAV) predisposes individuals to secondary infections with the bacterium Streptococcus pneumoniae (the pneumococcus). Infections may manifest as pneumonia, sepsis, meningitis or otitis media (OM). It remains controversial as to whether secondary pneumococcal disease is due to the induction of an aberrant immune response or IAV induced immunosuppression. Moreover, as the majority of studies have been performed in the context of pneumococcal pneumonia, it remains unclear how far these findings can be extrapolated to other pneumococcal disease phenotypes. Here, we demonstrate that the viral hemagglutinin (HA) mediates bacterial OM by inducing a pro-inflammatory response in the middle ear cavity in a replication-dependent manner. Importantly, our findings show that it is the inflammatory response that mediates pneumococcal replication; not viral suppression of the immune system or epithelial damage. This study provide the first evidence that HA induced inflammation drives pneumococcal replication in the middle ear cavity, which has important consequences to the treatment of pneumococcal OM.

2013-01-01 | GSE41098 | GEO

A2ML1 and otitis media: novel variants, differential expression, and relevant pathways.

Project description:A genetic basis for otitis media is established, however, the role of rare variants in disease etiology is largely unknown. Previously a duplication variant within A2ML1 was identified as a significant risk factor for otitis media in an indigenous Filipino population and in US children. In this report exome and Sanger sequencing was performed using DNA samples from the indigenous Filipino population, Filipino cochlear implantees, US probands, Finnish, and Pakistani families with otitis media. Sixteen novel, damaging A2ML1 variants identified in otitis media patients were rare or low-frequency in population-matched controls. In the indigenous population, both gingivitis and A2ML1 variants including the known duplication variant and the novel splice variant c.4061?+?1?G>C were independently associated with otitis media. Sequencing of salivary RNA samples from indigenous Filipinos demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants. Sequencing of additional salivary RNA samples from US patients with otitis media revealed differentially expressed genes that are highly correlated with A2ML1 expression levels. In particular, RND3 is upregulated in both A2ML1 variant carriers and high-A2ML1 expressors. These findings support a role for A2ML1 in keratinocyte differentiation within the middle ear as part of otitis media pathology and the potential application of ROCK inhibition in otitis media.

| S-EPMC6711784 | biostudies-literature

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