{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T05:58:45Z","timestamp":1790402325176,"version":"4.1.0"},"reference-count":160,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,29]],"date-time":"2021-10-29T00:00:00Z","timestamp":1635465600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Otitis media (OM) encompasses a spectrum of clinical presentations ranging from the readily identifiable Acute OM (AOM), which is characterised by otalgia and fever, to chronic otitis media with effusion (COME) where impaired hearing due to middle ear effusion may be the only clinical symptom. Chronic suppurative OM (CSOM) presents as a more severe form of OM, involving perforation of the tympanic membrane. The pathogenesis of OM in these varied clinical presentations is unclear but activation of the innate inflammatory responses to viral and\/or bacterial infection of the upper respiratory tract performs an integral role. This localised inflammatory response can persist even after pathogens are cleared from the middle ear, eustachian tubes and, in the case of respiratory viruses, even the nasal compartment. Children prone to OM may experience an over exuberant inflammatory response that underlies the development of chronic forms of OM and their sequelae, including hearing impairment. Treatments for chronic effusive forms of OM are limited, with current therapeutic guidelines recommending a \u201cwatch and wait\u201d strategy rather than active treatment with antibiotics, corticosteroids or other anti-inflammatory drugs. Overall, there is a clear need for more targeted and effective treatments that either prevent or reduce the hyper-inflammatory response associated with chronic forms of OM. Improved treatment options rely upon an in-depth understanding of OM pathogenesis, particularly the role of the host innate immune response during acute OM. In this paper, we review the current literature regarding the innate immune response within the middle ear to bacterial and viral otopathogens alone, and as co-infections. This is an important consideration, as the role of respiratory viruses as primary pathogens in OM is not yet fully understood. Furthermore, increased reporting from PCR-based diagnostics, indicates that viral\/bacterial co-infections in the middle ear are more common than bacterial infections alone. Increasingly, the mechanisms by which viral\/bacterial co-infections may drive or maintain complex innate immune responses and inflammation during OM as a chronic response require investigation. Improved understanding of the pathogenesis of chronic OM, including host innate immune response within the middle ear is vital for development of improved diagnostic and treatment options for our children.<\/jats:p>","DOI":"10.3389\/fcimb.2021.764772","type":"journal-article","created":{"date-parts":[[2021,10,29]],"date-time":"2021-10-29T06:09:37Z","timestamp":1635487777000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["Innate Immunity in the Middle Ear Mucosa"],"prefix":"10.3389","volume":"11","author":[{"given":"Helen M.","family":"Massa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten M.","family":"Spann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan W.","family":"Cripps","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1177\/1753425919866006","article-title":"Innate Immunity of Surfactant Protein A in Experimental Otitis Media","volume":"25","author":"Abdel-Razek","year":"2019","journal-title":"Innate Immun."},{"key":"B2","doi-asserted-by":"publisher","first-page":"e00102","DOI":"10.1128\/mBio.00102-10","article-title":"Indirect Pathogenicity of Haemophilus influenzae and Moraxella catarrhalis in Polymicrobial Otitis Media Occurs via Interspecies Quorum Signaling","volume":"1","author":"Armbruster","year":"2010","journal-title":"mBio"},{"key":"B3","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1189\/jlb.0709518","article-title":"Immunopathogenesis of Polymicrobial Otitis Media","volume":"87","author":"Bakaletz","year":"2010","journal-title":"J. Leukoc. Biol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1016\/j.prrv.2012.03.001","article-title":"Bacterial Biofilms in the Upper Airway - Evidence for Role in Pathology and Implications for Treatment of Otitis Media","volume":"13","author":"Bakaletz","year":"2012","journal-title":"Paediatr. Respir. Rev."},{"key":"B5","doi-asserted-by":"publisher","first-page":"4188","DOI":"10.1128\/iai.63.10.4188-4190.1995","article-title":"Adenovirus Serotype 1 Does Not Act Synergistically With Moraxella (Branhamella) Catarrhalis to Induce Otitis Media in the Chinchilla","volume":"63","author":"Bakaletz","year":"1995","journal-title":"Infect. Immun."},{"key":"B6","doi-asserted-by":"publisher","first-page":"ijms22020482","DOI":"10.3390\/ijms22020482","article-title":"Therapeutic Potential of Antimicrobial Peptides in Polymicrobial Biofilm-Associated Infections","volume":"22","author":"Batoni","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1007\/s40136-017-0152-6","article-title":"Streptococcus Pneumoniae Otitis Media Pathogenesis and How It Informs Our Understanding of Vaccine Strategies","volume":"5","author":"Bergenfelz","year":"2017","journal-title":"Curr. Otorhinolaryngol. Rep."},{"key":"B8","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1177\/0194599812449986","article-title":"Mouse Models of Otitis Media: Strengths and Limitations","volume":"147","author":"Bhutta","year":"2012","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1242\/dmm.029983","article-title":"Understanding the Aetiology and Resolution of Chronic Otitis Media From Animal and Human Studies","volume":"10","author":"Bhutta","year":"2017","journal-title":"Dis. Model Mech."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2334-11-161","article-title":"Viral-Bacterial Co-Infection in Australian Indigenous Children With Acute Otitis Media","volume":"11","author":"Binks","year":"2011","journal-title":"BMC Infect. Dis."},{"key":"B11","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1016\/0091-6749(88)90168-6","article-title":"Anatomy and Physiology of Eustachian Tube and Middle Ear Related to Otitis Media","volume":"81","author":"Bluestone","year":"1988","journal-title":"J. Allergy Clin. Immunol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.4049\/jimmunol.1800246","article-title":"Variation in Genome-Wide NF-kappaB RELA Binding Sites Upon Microbial Stimuli and Identification of a Virus Response Profile","volume":"201","author":"Borghini","year":"2018","journal-title":"J. Immunol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e40088","DOI":"10.1371\/journal.pone.0040088","article-title":"Respiratory Syncytial Virus Promotes Moraxella Catarrhalis-Induced Ascending Experimental Otitis Media","volume":"7","author":"Brockson","year":"2012","journal-title":"PloS One"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1288\/00005537-199410000-00021","article-title":"Otologic Manifestations of Experimental Rhinovirus Infection","volume":"104","author":"Buchman","year":"1994","journal-title":"Laryngoscope"},{"key":"B15","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1056\/NEJM198502213120802","article-title":"Acquired Ciliary Defects in Nasal Epithelium of Children With Acute Viral Upper Respiratory Infections","volume":"312","author":"Carson","year":"1985","journal-title":"N. Engl. J. Med."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD013053.pub2","article-title":"Topical Versus Systemic Antibiotics for Chronic Suppurative Otitis Media","volume":"2","author":"Chong","year":"2021","journal-title":"Cochrane Database Syst. Rev."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1097\/00006454-200010000-00013","article-title":"Viruses and Acute Otitis Media","volume":"19","author":"Chonmaitree","year":"2000","journal-title":"Pediatr. Infect. Dis. J."},{"key":"B18","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1097\/00006454-200003000-00020","article-title":"Detection of Respiratory Viruses in the Middle Ear Fluids of Children With Acute Otitis Media by Multiplex Reverse Transcription:Polymerase Chain Reaction Assay","volume":"19","author":"Chonmaitree","year":"2000","journal-title":"Pediatr. Infect. Dis. J."},{"key":"B19","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1086\/528685","article-title":"Viral Upper Respiratory Tract Infection and Otitis Media Complication in Young Children","volume":"46","author":"Chonmaitree","year":"2008","journal-title":"Clin. Infect. Dis."},{"key":"B20","doi-asserted-by":"publisher","first-page":"e20153555","DOI":"10.1542\/peds.2015-3555","article-title":"Acute Otitis Media and Other Complications of Viral Respiratory Infection","volume":"137","author":"Chonmaitree","year":"2016","journal-title":"Pediatrics"},{"key":"B21","doi-asserted-by":"publisher","first-page":"2351","DOI":"10.1002\/lary.25981","article-title":"Prevalence and Associated Factors of Chronic Suppurative Otitis Media: Data From the Korea National Health and Nutrition Examination Surve","volume":"126","author":"Chung","year":"2016","journal-title":"Laryngoscope"},{"key":"B22","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1016\/j.otohns.2007.02.009","article-title":"The Role of Chronic Infection in Children With Otitis Media With Effusion: Evidence for Intracellular Persistence of Bacteria","volume":"138","author":"Coates","year":"2008","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1016\/j.vaccine.2012.12.078","article-title":"High Pneumococcal Serotype Specific IgG, IgG1 and IgG2 Levels in Serum and the Middle Ear of Children With Recurrent Acute Otitis Media Receiving Ventilation Tubes","volume":"31","author":"Corscadden","year":"2013","journal-title":"Vaccine"},{"key":"B24","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1177\/000348949410300111","article-title":"Nasal and Otologic Effects of Experimental Influenza A Virus Infection","volume":"103","author":"Doyle","year":"1994","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/srep33240","article-title":"Genome-Wide Association Analysis Reveals Variants on Chromosome 19 That Contribute to Childhood Risk of Chronic Otitis Media With Effusion","volume":"6","author":"Einarsdottir","year":"2016","journal-title":"Sci. Rep."},{"key":"B26","doi-asserted-by":"publisher","first-page":"814","DOI":"10.1542\/peds.2007-0524","article-title":"Genetic Polymorphisms in Immunoresponse Genes TNFA, IL6, IL10, and TLR4 are Associated With Recurrent Acute Otitis Media","volume":"120","author":"Emonts","year":"2007","journal-title":"Pediatrics"},{"key":"B27","doi-asserted-by":"publisher","first-page":"e00147","DOI":"10.1128\/IAI.00147-20","article-title":"Niche- and Gender-Dependent Immune Reactions in Relation to the Microbiota Profile in Pediatric Patients With Otitis Media With Effusion","volume":"88","author":"Enoksson","year":"2020","journal-title":"Infect. Immun."},{"key":"B28","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1016\/j.pharmthera.2008.11.001","article-title":"Airway Mucus: The Good, the Bad, the Sticky","volume":"121","author":"Evans","year":"2009","journal-title":"Pharmacol. Ther."},{"key":"B29","first-page":"152","article-title":"Infiltration of Immunocompetent Cells in the Middle Ear During Acute Otitis Media: A Temporal Study","volume":"20","author":"Forseni","year":"1999","journal-title":"Am. J. Otol."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2019.01395","article-title":"Current Understanding of Host Genetics of Otitis Media","volume":"10","author":"Geng","year":"2019","journal-title":"Front. Genet."},{"key":"B31","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1177\/000348948709600212","article-title":"Eustachian Tube Histopathology During Experimental Influenza A Virus Infection in the Chinchilla","volume":"96","author":"Giebink","year":"1987","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1128\/iai.41.3.913-920.1983","article-title":"Different Virulence of Influenza A Virus Strains and Susceptibility to Pneumococcal Otitis Media in Chinchillas","volume":"41","author":"Giebink","year":"1983","journal-title":"Infect. Immun."},{"key":"B33","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1007\/s40136-017-0151-7","article-title":"Recurrent Acute Otitis Media: What Are the Options for Treatment and Prevention","volume":"5","author":"Granath","year":"2017","journal-title":"Curr. Otorhinolaryngol. Rep."},{"key":"B34","doi-asserted-by":"publisher","first-page":"e0132551","DOI":"10.1371\/journal.pone.0132551","article-title":"Predisposition to Childhood Otitis Media and Genetic Polymorphisms Within the Toll-Like Receptor 4 (TLR4) Locus","volume":"10","author":"Hafren","year":"2015","journal-title":"PloS One"},{"key":"B35","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1001\/jama.296.2.202","article-title":"Direct Detection of Bacterial Biofilms on the Middle-Ear Mucosa of Children With Chronic Otitis Media","volume":"296","author":"Hall-Stoodley","year":"2006","journal-title":"JAMA"},{"key":"B36","doi-asserted-by":"publisher","first-page":"S51","DOI":"10.1016\/s0264-410x(00)00278-4","article-title":"The Role of Respiratory Viruses in Otitis Media","author":"Heikkinen","year":"2000","journal-title":"Vaccine"},{"key":"B37","doi-asserted-by":"publisher","first-page":"157","DOI":"10.3109\/07853890008998822","article-title":"Increasing Importance of Viruses in Acute Otitis Media","volume":"32","author":"Heikkinen","year":"2000","journal-title":"Ann. Med."},{"key":"B38","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1128\/CMR.16.2.230-241.2003","article-title":"Importance of Respiratory Viruses in Acute Otitis Media","volume":"16","author":"Heikkinen","year":"2003","journal-title":"Clin. Microbiol. Rev."},{"key":"B39","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1056\/NEJM199901283400402","article-title":"Prevalence of Various Respiratory Viruses in the Middle Ear During Acute Otitis Media","volume":"340","author":"Heikkinen","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1862","DOI":"10.1086\/593213","article-title":"Myeloid Differentiation Primary Response Gene 88 is Required for the Resolution of Otitis Media","volume":"198","author":"Hernandez","year":"2008","journal-title":"J. Infect. Dis."},{"key":"B41","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1186\/s12864-015-1475-7","article-title":"The Transcriptome of a Complete Episode of Acute Otitis Media","volume":"16","author":"Hernandez","year":"2015","journal-title":"BMC Genomics"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2431-12-87","article-title":"One Third of Middle Ear Effusions From Children Undergoing Tympanostomy Tube Placement had Multiple Bacterial Pathogens","volume":"12","author":"Holder","year":"2012","journal-title":"BMC Pediatr."},{"key":"B43","doi-asserted-by":"publisher","first-page":"886","DOI":"10.1038\/pr.2016.154","article-title":"TLR2 Promotes Macrophage Recruitment and Streptococcus Pneumoniae Clearance During Mouse Otitis Media","volume":"80","author":"Huang","year":"2016","journal-title":"Pediatr. Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1001\/archotol.1990.01870030088015","article-title":"Analysis of Immunocompetent Cells in the Middle Ear Mucosa","volume":"116","author":"Ichimiya","year":"1990","journal-title":"Arch. Otolaryngol. Head Neck Surg."},{"key":"B45","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/s0196-0709(97)90077-6","article-title":"Immunological Potential of the Tympanic Membrane. Observation Under Normal and Inflammatory Conditions","volume":"18","author":"Ichimiya","year":"1997","journal-title":"Am. J. Otolaryngol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.ijporl.2017.03.018","article-title":"Monophosphoryl Lipid A Enhances Nontypeable Haemophilus Influenzae-Specific Mucosal and Systemic Immune Responses by Intranasal Immunization","volume":"97","author":"Iwasaki","year":"2017","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"443","DOI":"10.3109\/00016489609137871","article-title":"The Mucosa of the Middle Ear and Eustachian Tube in the Young Rat: Number of Granulocytes, Macrophages, Dendritic Cells, NK Cells and T and B Lymphocytes in Healthy Animals and During Otitis Media","volume":"116","author":"Jecker","year":"1996","journal-title":"Acta Otolaryngol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1046\/j.1365-2249.2001.01543.x","article-title":"Proliferating Macrophages, Dendritic Cells, Natural Killer Cells, T and B Lymphocytes in the Middle Ear and Eustachian Tube Mucosa During Experimental Acute Otitis Media in the Rat","volume":"126","author":"Jecker","year":"2001","journal-title":"Clin. Exp. Immunol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"e00456-19","DOI":"10.1128\/mSphere.00456-19","article-title":"Examining the Evidence for an Adult Healthy Middle Ear Microbiome","volume":"4","author":"Jervis-Bardy","year":"2019","journal-title":"mSphere"},{"key":"B50","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.ijporl.2018.12.030","article-title":"Pathogen Reservoir Hypothesis Investigated by Analyses of the Adenotonsillar and Middle Ear Microbiota","volume":"118","author":"Johnston","year":"2019","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1128\/IAI.00660-10","article-title":"Nontypeable Haemophilus Influenzae Initiates Formation of Neutrophil Extracellular Traps","volume":"79","author":"Juneau","year":"2011","journal-title":"Infect. Immun."},{"key":"B52","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1097\/INF.0b013e3181f253d5","article-title":"Clinical Spectrum of Acute Otitis Media Complicating Upper Respiratory Tract Viral Infection","volume":"30","author":"Kalu","year":"2011","journal-title":"Pediatr. Infect. Dis. J."},{"key":"B53","doi-asserted-by":"publisher","first-page":"E39","DOI":"10.1002\/lary.24920","article-title":"Cytokine, Chemokine, and Toll-Like Receptor Expression in Middle Ear Fluids of Children With Acute Otitis Media","volume":"125","author":"Kaur","year":"2015","journal-title":"Laryngoscope"},{"key":"B54","doi-asserted-by":"publisher","first-page":"pii: peds.2017","DOI":"10.1542\/peds.2017-0181","article-title":"Epidemiology of Acute Otitis Media in the Postpneumococcal Conjugate Vaccine Era","volume":"140","author":"Kaur","year":"2017","journal-title":"Pediatrics"},{"key":"B55","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1093\/intimm\/dxp017","article-title":"The Roles of TLRs, RLRs and NLRs in Pathogen Recognition","volume":"21","author":"Kawai","year":"2009","journal-title":"Int. Immunol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.ijporl.2014.12.015","article-title":"Age-Dependent Changes in Pattern Recognition Receptor and Cytokine mRNA Expression in Children With Otitis Media With Effusion","volume":"79","author":"Kim","year":"2015","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"B57","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3342\/ceo.2014.7.1.7","article-title":"Decreased Pattern-Recognition Receptor-Mediated Cytokine mRNA Expression in Obese Children With Otitis Media With Effusion","volume":"7","author":"Kim","year":"2014","journal-title":"Clin. Exp. Otorhinolaryngol."},{"key":"B58","doi-asserted-by":"publisher","first-page":"1425","DOI":"10.1016\/j.ijporl.2010.09.026","article-title":"TLR-9, NOD-1, NOD-2, RIG-I and Immunoglobulins in Recurrent Otitis Media With Effusion","volume":"74","author":"Kim","year":"2010","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1203\/PDR.0b013e3182055237","article-title":"Pneumococcal Peptidoglycan-Polysaccharides Regulate Toll-Like Receptor 2 in the Mouse Middle Ear Epithelial Cells","volume":"69","author":"Komori","year":"2011","journal-title":"Pediatr. Res."},{"key":"B60","doi-asserted-by":"publisher","first-page":"S39","DOI":"10.5694\/j.1326-5377.2009.tb02925.x","article-title":"Natural History, Definitions, Risk Factors and Burden of Otitis Media","volume":"191","author":"Kong","year":"2009","journal-title":"Med. J. Aust."},{"key":"B61","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1288\/00005537-199106000-00013","article-title":"Type B Haemophilus Influenzae-Induced Otitis Media in the Mouse","volume":"101","author":"Krekorian","year":"1991","journal-title":"Laryngoscope"},{"key":"B62","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1016\/j.micinf.2009.03.001","article-title":"The Incidence of Streptococcus Pneumoniae Otitis Media is Affected by the Polymicrobial Environment Particularly Moraxella Catarrhalis in a Mouse Nasal Colonisation Model","volume":"11","author":"Krishnamurthy","year":"2009","journal-title":"Microbes Infect."},{"key":"B63","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3109\/1040841X.2012.706249","article-title":"Recognition of Bacterial Infection by Innate Immune Sensors","volume":"39","author":"Kumar","year":"2013","journal-title":"Crit. Rev. Microbiol."},{"key":"B64","doi-asserted-by":"publisher","first-page":"16","DOI":"10.3109\/08830185.2010.529976","article-title":"Pathogen Recognition by the Innate Immune System","volume":"30","author":"Kumar","year":"2011","journal-title":"Int. Rev. Immunol."},{"key":"B65","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1007\/s11882-015-0585-2","article-title":"Innate Immunity: Orchestrating Inflammation and Resolution of Otitis Media","volume":"16","author":"Kurabi","year":"2016","journal-title":"Curr. Allergy Asthma Rep."},{"key":"B66","first-page":"147","article-title":"The Role of Adenoids in Nasopharyngeal Colonization With Nontypeable Haemophilus Influenzae","volume":"523","author":"Kurono","year":"1996","journal-title":"Acta Otolaryngol. Suppl."},{"key":"B67","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1016\/j.bbrc.2006.10.052","article-title":"Synergistic Activation of NF-kappaB by Nontypeable H. Influenzae and S. Pneumoniae is Mediated by CK2, IKKbeta-IkappaBalpha, and P38 MAPK","volume":"351","author":"Kweon","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2431-8-23","article-title":"Compared to Placebo, Long-Term Antibiotics Resolve Otitis Media With Effusion (OME) and Prevent Acute Otitis Media With Perforation (AOMwiP) in a High-Risk Population: A Randomized Controlled Trial","volume":"8","author":"Leach","year":"2008","journal-title":"BMC Pediatr."},{"key":"B69","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1177\/000348941112000310","article-title":"Activation of the Transforming Growth Factor Beta Pathway in Bacterial Otitis Media","volume":"120","author":"Lee","year":"2011","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"B70","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1177\/1753425919872266","article-title":"NOD1\/NOD2-Mediated Recognition of non-Typeable Haemophilus Influenzae Activates Innate Immunity During Otitis Media","volume":"25","author":"Lee","year":"2019","journal-title":"Innate Immun."},{"key":"B71","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1016\/j.bbrc.2004.08.144","article-title":"Antibiotic Activity and Structural Analysis of the Scorpion-Derived Antimicrobial Peptide IsCT and its Analogs","volume":"323","author":"Lee","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2334-8-87","article-title":"Induction of Beta Defensin 2 by NTHi Requires TLR2 Mediated MyD88 and IRAK-TRAF6-P38mapk Signaling Pathway in Human Middle Ear Epithelial Cells","volume":"8","author":"Lee","year":"2008","journal-title":"BMC Infect. Dis."},{"key":"B73","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1177\/1753425910393539","article-title":"The Role of DNA Sensing and Innate Immune Receptor TLR9 in Otitis Media","volume":"18","author":"Leichtle","year":"2012","journal-title":"Innate Immun."},{"key":"B74","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1177\/1753425909103170","article-title":"TLR4-Mediated Induction of TLR2 Signaling is Critical in the Pathogenesis and Resolution of Otitis Media","volume":"15","author":"Leichtle","year":"2009","journal-title":"Innate Immun."},{"key":"B75","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1007\/s11882-010-0158-3","article-title":"Innate Signaling in Otitis Media: Pathogenesis and Recovery","volume":"11","author":"Leichtle","year":"2011","journal-title":"Curr. Allergy Asthma Rep."},{"key":"B76","doi-asserted-by":"publisher","first-page":"ijms22147688","DOI":"10.3390\/ijms22147688","article-title":"Roles of PRR-Mediated Signaling Pathways in the Regulation of Oxidative Stress and Inflammatory Diseases","volume":"22","author":"Li","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B77","doi-asserted-by":"publisher","first-page":"e964","DOI":"10.1542\/peds.2012-3488","article-title":"The Diagnosis and Management of Acute Otitis Media","volume":"131","author":"Lieberthal","year":"2013","journal-title":"Pediatrics"},{"key":"B78","doi-asserted-by":"publisher","first-page":"E52","DOI":"10.1177\/0194599813479772","article-title":"Panel 4: Recent Advances in Otitis Media in Molecular Biology, Biochemistry, Genetics, and Animal Models","volume":"148","author":"Li","year":"2013","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"B79","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1177\/00034894760850S209","article-title":"Functional Morphology of the Mucosa of the Middle Ear and Eustachian Tube","volume":"85","author":"Lim","year":"1976","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"B80","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1111\/j.1365-2273.1979.tb01888.x","article-title":"Normal and Pathological Mucosa of the Middle Ear and Eustachian Tube","volume":"4","author":"Lim","year":"1979","journal-title":"Clin. Otolaryngol. Allied Sci."},{"key":"B81","doi-asserted-by":"publisher","first-page":"S17","DOI":"10.1016\/s0264-410x(00)00273-5","article-title":"Cell Biology of Tubotympanum in Relation to Pathogenesis of Otitis Media - a Review","author":"Lim","year":"2000","journal-title":"Vaccine"},{"key":"B82","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1038\/emm.2007.27","article-title":"Toll-Like Receptor 9 Dependent Activation of MAPK and NF-kB is Required for the CpG ODN-Induced Matrix Metalloproteinase-9 Expression","volume":"39","author":"Lim","year":"2007","journal-title":"Exp. Mol. Med."},{"key":"B83","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1038\/mi.2008.5","article-title":"Mucins in the Mucosal Barrier to Infection","volume":"1","author":"Linden","year":"2008","journal-title":"Mucosal Immunol."},{"key":"B84","doi-asserted-by":"publisher","first-page":"S41","DOI":"10.1177\/0194599816685559","article-title":"Panel 3: Genetics and Precision Medicine of Otitis Media","volume":"156","author":"Lin","year":"2017","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"B85","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1093\/intimm\/dxs154","article-title":"Transcriptome Signature in Young Children With Acute Otitis Media Due to non-Typeable Haemophilus Influenzae","volume":"25","author":"Liu","year":"2013","journal-title":"Int. Immunol."},{"key":"B86","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1371\/journal.ppat.0010001","article-title":"The Role of Innate Immune Responses in the Outcome of Interspecies Competition for Colonization of Mucosal Surfaces","volume":"1","author":"Lysenko","year":"2005","journal-title":"PloS Pathog."},{"key":"B87","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.heares.2006.05.012","article-title":"Evaluation of the Mouse Model for Acute Otitis Media","volume":"219","author":"MacArthur","year":"2006","journal-title":"Hear. Res."},{"key":"B88","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1002\/lary.21349","article-title":"Altered Expression of Middle and Inner Ear Cytokines in Mouse Otitis Media","volume":"121","author":"MacArthur","year":"2011","journal-title":"Laryngoscope"},{"key":"B89","doi-asserted-by":"publisher","first-page":"248","DOI":"10.3892\/ijmm.2018.3577","article-title":"Quercetin Inhibits NTHi-Triggered CXCR4 Activation Through Suppressing IKKalpha\/NF-kappaB and MAPK Signaling Pathways in Otitis Media","volume":"42","author":"Ma","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"B90","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/j.ijporl.2007.12.008","article-title":"The Incidence, Prevalence and Burden of OM in Unselected Children Aged 1\u20138 Years Followed by Weekly Otoscopy Through the \u201cCommon Cold\u201d Season","volume":"72","author":"Mandel","year":"2008","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijporl.2019.109836","article-title":"Panel 4: Recent Advances in Understanding the Natural History of the Otitis Media Microbiome and its Response to Environmental Pressures","author":"Marsh","year":"2020","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"B92","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.anorl.2017.03.010","article-title":"Tubotympanic System Functioning","volume":"134","author":"Martin","year":"2017","journal-title":"Eur. Ann. Otorhinolaryngol. Head Neck Dis."},{"key":"B93","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1016\/B978-0-12-415847-4.00101-4","article-title":"Chapter 101: Middle Ear and Eustachian Tube Mucosal Immunology","volume-title":"Mucosal Immunology","author":"Massa","year":"2015"},{"key":"B94","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1001\/archotol.1989.01860330044014","article-title":"Alterations of the Eustachian Tube, Middle Ear, and Nose in Rhinovirus Infection","volume":"115","author":"McBride","year":"1989","journal-title":"Arch. Otolaryngol. Head Neck Surg."},{"key":"B95","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1016\/j.ijporl.2011.02.021","article-title":"Acute Otitis Media Severity: Association With Cytokine Gene Polymorphisms and Other Risk Factors","volume":"75","author":"McCormick","year":"2011","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"B96","doi-asserted-by":"publisher","first-page":"1399","DOI":"10.1111\/j.1462-5822.2009.01339.x","article-title":"Respiratory Syncytial Virus-Induced Dysregulation of Expression of a Mucosal Beta-Defensin Augments Colonization of the Upper Airway by non-Typeable Haemophilus Influenzae","volume":"11","author":"McGillivary","year":"2009","journal-title":"Cell Microbiol."},{"key":"B97","doi-asserted-by":"publisher","first-page":"2446","DOI":"10.1016\/j.molimm.2006.10.008","article-title":"A Member of the Cathelicidin Family of Antimicrobial Peptides is Produced in the Upper Airway of the Chinchilla and its mRNA Expression is Altered by Common Viral and Bacterial Co-Pathogens of Otitis Media","volume":"44","author":"McGillivary","year":"2007","journal-title":"Mol. Immunol."},{"key":"B98","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1038\/nature06246","article-title":"Recognition of Microorganisms and Activation of the Immune Response","volume":"449","author":"Medzhitov","year":"2007","journal-title":"Nature"},{"key":"B99","doi-asserted-by":"publisher","first-page":"e1005797","DOI":"10.1371\/journal.ppat.1005797","article-title":"Compromised Defenses: Exploitation of Epithelial Responses During Viral-Bacterial Co-Infection of the Respiratory Tract","volume":"12","author":"Melvin","year":"2016","journal-title":"PloS Pathog."},{"key":"B100","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/j.ijid.2014.10.015","article-title":"Role of Innate Immunity in the Pathogenesis of Otitis Media","volume":"29","author":"Mittal","year":"2014","journal-title":"Int. J. Infect. Dis."},{"key":"B101","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1016\/j.jgg.2014.10.003","article-title":"Immunity Genes and Susceptibility to Otitis Media: A Comprehensive Review","volume":"41","author":"Mittal","year":"2014","journal-title":"J. Genet. Genomics"},{"key":"B102","doi-asserted-by":"publisher","first-page":"e36226","DOI":"10.1371\/journal.pone.0036226","article-title":"Burden of Disease Caused by Otitis Media: Systematic Review and Global Estimates","volume":"7","author":"Monasta","year":"2012","journal-title":"PloS One"},{"key":"B103","doi-asserted-by":"publisher","first-page":"3361","DOI":"10.1128\/IAI.01886-06","article-title":"Toll-Like Receptor 2-Dependent NF-kappaB Activation is Involved in Nontypeable Haemophilus Influenzae-Induced Monocyte Chemotactic Protein 1 Up-Regulation in the Spiral Ligament Fibrocytes of the Inner Ear","volume":"75","author":"Moon","year":"2007","journal-title":"Infect. Immun."},{"key":"B104","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1097\/INF.0b013e3181d067cb","article-title":"The Interaction Between Respiratory Viruses and Pathogenic Bacteria in the Upper Respiratory Tract of Asymptomatic Aboriginal and non-Aboriginal Children","volume":"29","author":"Moore","year":"2010","journal-title":"Pediatr. Infect. Dis. J."},{"key":"B105","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/2049-632X.12216","article-title":"Replication of Type 5 Adenovirus Promotes Middle Ear Infection by Streptococcus Pneumoniae in the Chinchilla Model of Otitis Media","volume":"73","author":"Murrah","year":"2015","journal-title":"Pathog. Dis."},{"key":"B106","doi-asserted-by":"publisher","first-page":"e0150949","DOI":"10.1371\/journal.pone.0150949","article-title":"Predominant Bacteria Detected From the Middle Ear Fluid of Children Experiencing Otitis Media: A Systematic Review","volume":"11","author":"Ngo","year":"2016","journal-title":"PloS One"},{"key":"B107","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1097\/MOP.0000000000000184","article-title":"Importance of Viruses in Acute Otitis Media","volume":"27","author":"Nokso-Koivisto","year":"2015","journal-title":"Curr. Opin. Pediatr."},{"key":"B108","doi-asserted-by":"publisher","first-page":"CVI.00563-16","DOI":"10.1128\/CVI.00563-16","article-title":"Transcutaneous Immunization With a Band-Aid Prevents Experimental Otitis Media in a Polymicrobial Model","volume":"24","author":"Novotny","year":"2017","journal-title":"Clin. Vaccine Immunol."},{"key":"B109","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1001\/archotol.1981.00790450004003","article-title":"Inflammatory Cells in the Middle Ear Mucosa in Cases of Chronic Otitis Media","volume":"107","author":"Palva","year":"1981","journal-title":"Arch. Otolaryngol."},{"key":"B110","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1002\/JLB.4RU0119-003R","article-title":"Subversion of Host Immune Responses by Otopathogens During Otitis Media","volume":"106","author":"Parrish","year":"2019","journal-title":"J. Leukoc. Biol."},{"key":"B111","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/0165-5876(92)90075-z","article-title":"Effect of Respiratory Syncytial Virus on Adherence, Colonization and Immunity of non-Typable Haemophilus Influenzae: Implications for Otitis Media","volume":"23","author":"Patel","year":"1992","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"B112","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1097\/INF.0b013e318194b7c6","article-title":"Systemic Cytokine Response Profiles Associated With Respiratory Virus-Induced Acute Otitis Media","volume":"28","author":"Patel","year":"2009","journal-title":"Pediatr. Infect. Dis. J."},{"key":"B113","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1097\/INF.0b013e3181aa5b13","article-title":"Nasopharyngeal Acute Phase Cytokines in Viral Upper Respiratory Infection: Impact on Acute Otitis Media in Children","volume":"28","author":"Patel","year":"2009","journal-title":"Pediatr. Infect. Dis. J."},{"key":"B114","doi-asserted-by":"publisher","first-page":"3750","DOI":"10.1128\/JCM.01186-11","article-title":"Viral-Bacterial Interactions and Risk of Acute Otitis Media Complicating Upper Respiratory Tract Infection","volume":"49","author":"Pettigrew","year":"2011","journal-title":"J. Clin. Microbiol."},{"key":"B115","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1016\/j.jinf.2020.03.017","article-title":"Immunologic Dysfunction Contributes to the Otitis Prone Condition","volume":"80","author":"Pichichero","year":"2020","journal-title":"J. Infect."},{"key":"B116","doi-asserted-by":"publisher","first-page":"S106","DOI":"10.1177\/0194599816658290","article-title":"Panel 8: Report on Recent Advances in Molecular and Cellular Biochemistry","volume":"156","author":"Preciado","year":"2017","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"B117","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1067\/mpd.2001.110133","article-title":"Surfactant Protein-A Gene Locus Associated With Recurrent Otitis Media","volume":"138","author":"Ramet","year":"2001","journal-title":"J. Pediatr."},{"key":"B118","doi-asserted-by":"publisher","first-page":"3429","DOI":"10.1073\/pnas.0500599102","article-title":"Synergistic Proinflammatory Responses Induced by Polymicrobial Colonization of Epithelial Surfaces","volume":"102","author":"Ratner","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B119","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.512743","article-title":"A Bacterial Epigenetic Switch in Non-Typeable Haemophilus Influenzae Modifies Host Immune Response During Otitis Media","volume":"10","author":"Robledo-Avila","year":"2020","journal-title":"Front. Cell Infect. Microbiol."},{"key":"B120","doi-asserted-by":"publisher","first-page":"S1","DOI":"10.1177\/0194599815623467","article-title":"Clinical Practice Guideline: Otitis Media With Effusion (Update)","volume":"154","author":"Rosenfeld","year":"2016","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"B121","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/j.jinf.2012.12.002","article-title":"Bacterial and Viral Interactions Within the Nasopharynx Contribute to the Risk of Acute Otitis Media","volume":"66","author":"Ruohola","year":"2013","journal-title":"J. Infect."},{"key":"B122","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2020.00358","article-title":"Single-Cell Transcriptomes Reveal a Complex Cellular Landscape in the Middle Ear and Differential Capacities for Acute Response to Infection","volume":"11","author":"Ryan","year":"2020","journal-title":"Front. Genet."},{"key":"B123","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1097\/INF.0000000000002486","article-title":"Comprehensive Detection of Respiratory Bacterial and Viral Pathogens in the Middle Ear Fluid and Nasopharynx of Pediatric Patients With Acute Otitis Media","volume":"38","author":"Sawada","year":"2019","journal-title":"Pediatr. Infect. Dis. J."},{"key":"B124","doi-asserted-by":"publisher","first-page":"990","DOI":"10.1001\/jamaoto.2017.1320","article-title":"Neutrophil Extracellular Traps and Fibrin in Otitis Media: Analysis of Human and Chinchilla Temporal Bones","volume":"143","author":"Schachern","year":"2017","journal-title":"JAMA Otolaryngol. Head Neck Surg."},{"key":"B125","doi-asserted-by":"publisher","first-page":"3705","DOI":"10.1002\/1873-3468.12455","article-title":"Composition and Immunological Significance of the Upper Respiratory Tract Microbiota","volume":"590","author":"Schenck","year":"2016","journal-title":"FEBS Lett."},{"key":"B126","doi-asserted-by":"publisher","first-page":"16063","DOI":"10.1038\/nrdp.2016.63","article-title":"Otitis Media","volume":"2","author":"Schilder","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"B127","doi-asserted-by":"publisher","first-page":"e0227080","DOI":"10.1371\/journal.pone.0227080","article-title":"High Concentrations of Middle Ear Antimicrobial Peptides and Proteins and Proinflammatory Cytokines are Associated With Detection of Middle Ear Pathogens in Children With Recurrent Acute Otitis Media","volume":"14","author":"Seppanen","year":"2019","journal-title":"PloS One"},{"key":"B128","doi-asserted-by":"publisher","first-page":"7161","DOI":"10.1128\/IAI.70.12.7161-7164.2002","article-title":"Neuraminidase Expressed by Streptococcus Pneumoniae Desialylates the Lipopolysaccharide of Neisseria Meningitidis and Haemophilus Influenzae: A Paradigm for Interbacterial Competition Among Pathogens of the Human Respiratory Tract","volume":"70","author":"Shakhnovich","year":"2002","journal-title":"Infect. Immun."},{"key":"B129","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2334-8-134","article-title":"Lysozyme M Deficiency Leads to an Increased Susceptibility to Streptococcus Pneumoniae-Induced Otitis Media","volume":"8","author":"Shimada","year":"2008","journal-title":"BMC Infect. Dis."},{"key":"B130","doi-asserted-by":"publisher","first-page":"1857","DOI":"10.1093\/infdis\/jir618","article-title":"Influenza Virus Induces Bacterial and Nonbacterial Otitis Media","volume":"204","author":"Short","year":"2011","journal-title":"J. Infect. Dis."},{"key":"B131","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1128\/IAI.01278-12","article-title":"Influenza-Induced Inflammation Drives Pneumococcal Otitis Media","volume":"81","author":"Short","year":"2013","journal-title":"Infect. Immun."},{"key":"B132","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1016\/j.humimm.2014.05.009","article-title":"Attenuated TLRs in Middle Ear Mucosa Contributes to Susceptibility of Chronic Suppurative Otitis Media","volume":"75","author":"Si","year":"2014","journal-title":"Hum. Immunol."},{"key":"B133","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1111\/cei.12578","article-title":"Single Nucleotide Polymorphisms of Toll-Like Receptors and Susceptibility to Infectious Diseases","volume":"180","author":"Skevaki","year":"2015","journal-title":"Clin. Exp. Immunol."},{"key":"B134","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1016\/j.ijporl.2009.02.017","article-title":"Differential Expression of Toll-Like Receptors 2 and 4 in Rat Middle Ear","volume":"73","author":"Song","year":"2009","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"B135","doi-asserted-by":"publisher","first-page":"antibiotics10010052","DOI":"10.3390\/antibiotics10010052","article-title":"From Evidence to Clinical Guidelines in Antibiotic Treatment in Acute Otitis Media in Children","volume":"10","author":"Spoiala","year":"2021","journal-title":"Antibiotics (Basel)"},{"key":"B136","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1097\/INF.0b013e31827d104e","article-title":"Seasonality of Acute Otitis Media and the Role of Respiratory Viral Activity in Children","volume":"32","author":"Stockmann","year":"2013","journal-title":"Pediatr. Infect. Dis. J."},{"key":"B137","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1097\/00005537-200102000-00019","article-title":"Mucosal Immunity of the Middle Ear: Analysis at the Single Cell Level","volume":"111","author":"Suenaga","year":"2001","journal-title":"Laryngoscope"},{"key":"B138","doi-asserted-by":"publisher","first-page":"1710","DOI":"10.1128\/iai.62.5.1710-1718.1994","article-title":"Synergistic Effect of Adenovirus Type 1 and Nontypeable Haemophilus Influenzae in a Chinchilla Model of Experimental Otitis Media","volume":"62","author":"Suzuki","year":"1994","journal-title":"Infect. Immun."},{"key":"B139","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.3109\/00016480802669552","article-title":"Acute Tympanic Membrane Perforations and the Early Immunological Response in Rats","volume":"129","author":"Tahar Aissa","year":"2009","journal-title":"Acta Otolaryngol."},{"key":"B140","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1186\/1471-2431-11-94","article-title":"Multi-Species Bacterial Biofilm and Intracellular Infection in Otitis Media","volume":"11","author":"Thornton","year":"2011","journal-title":"BMC Pediatr. 11"},{"key":"B141","doi-asserted-by":"publisher","first-page":"e53837","DOI":"10.1371\/journal.pone.0053837","article-title":"Neutrophil Extracellular Traps and Bacterial Biofilms in Middle Ear Effusion of Children With Recurrent Acute Otitis Media\u2013a Potential Treatment Target","volume":"8","author":"Thornton","year":"2013","journal-title":"PloS One"},{"key":"B142","doi-asserted-by":"publisher","first-page":"e114","DOI":"10.1097\/INF.0000000000001479","article-title":"Polymorphisms of Mannose-Binding Lectin and Toll-Like Receptors 2, 3, 4, 7 and 8 and the Risk of Respiratory Infections and Acute Otitis Media in Children","volume":"36","author":"Toivonen","year":"2017","journal-title":"Pediatr. Infect. Dis. J."},{"key":"B143","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1177\/000348940010901106","article-title":"Effect of Adenovirus Type 1 and Influenza A Virus on Streptococcus Pneumoniae Nasopharyngeal Colonization and Otitis Media in the Chinchilla","volume":"109","author":"Tong","year":"2000","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"B144","doi-asserted-by":"publisher","first-page":"e95160","DOI":"10.1371\/journal.pone.0095160","article-title":"Deletion of the Complement C5a Receptor Alleviates the Severity of Acute Pneumococcal Otitis Media Following Influenza A Virus Infection in Mice","volume":"9","author":"Tong","year":"2014","journal-title":"PloS One"},{"key":"B145","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.micpath.2004.06.012","article-title":"Alteration of Gene Expression in Human Middle Ear Epithelial Cells Induced by Influenza A Virus and its Implication for the Pathogenesis of Otitis Media","volume":"37","author":"Tong","year":"2004","journal-title":"Microb. Pathog."},{"key":"B146","doi-asserted-by":"publisher","first-page":"4289","DOI":"10.1128\/IAI.71.8.4289-4296.2003","article-title":"Expression of Cytokine and Chemokine Genes by Human Middle Ear Epithelial Cells Induced by Influenza A Virus and Streptococcus Pneumoniae Opacity Variants","volume":"71","author":"Tong","year":"2003","journal-title":"Infect. Immun."},{"key":"B147","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.heares.2015.04.006","article-title":"Correlative mRNA and Protein Expression of Middle and Inner Ear Inflammatory Cytokines During Mouse Acute Otitis Media","volume":"326","author":"Trune","year":"2015","journal-title":"Hear. Res."},{"key":"B148","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.brainres.2009.02.047","article-title":"Mouse Models for Human Otitis Media","volume":"1277","author":"Trune","year":"2009","journal-title":"Brain Res."},{"key":"B149","doi-asserted-by":"publisher","first-page":"6930","DOI":"10.1038\/onc.2008.344","article-title":"Tight Junction-Based Epithelial Microenvironment and Cell Proliferation","volume":"27","author":"Tsukita","year":"2008","journal-title":"Oncogene"},{"key":"B150","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1007\/s11882-013-0360-1","article-title":"What Have We Learned From Murine Models of Otitis Media","volume":"13","author":"Tyrer","year":"2013","journal-title":"Curr. Allergy Asthma Rep."},{"key":"B151","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1002\/lary.20688","article-title":"Mucin Gene Polymorphisms in Otitis Media Patients","volume":"120","author":"Ubell","year":"2010","journal-title":"Laryngoscope"},{"key":"B152","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1007\/s11882-011-0223-6","article-title":"Innate Immunity and the Role of Defensins in Otitis Media","volume":"11","author":"Underwood","year":"2011","journal-title":"Curr. Allergy Asthma Rep."},{"key":"B153","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1038\/s41390-018-0060-6","article-title":"Characterization of Mucoid and Serous Middle Ear Effusions From Patients With Chronic Otitis Media: Implication of Different Biological Mechanisms","volume":"84","author":"Val","year":"2018","journal-title":"Pediatr. Res."},{"key":"B154","doi-asserted-by":"publisher","first-page":"1344","DOI":"10.1016\/j.jaci.2006.01.031","article-title":"Functional Polymorphisms in the Mannan-Binding Lectin 2 Gene: Effect on MBL Levels and Otitis Media","volume":"117","author":"Wiertsema","year":"2006","journal-title":"J. Allergy Clin. Immunol."},{"key":"B155","doi-asserted-by":"publisher","first-page":"e90933","DOI":"10.1371\/journal.pone.0090933","article-title":"NOD2\/RICK-Dependent Beta-Defensin 2 Regulation is Protective for Nontypeable Haemophilus Influenzae-Induced Middle Ear Infection","volume":"9","author":"Woo","year":"2014","journal-title":"PloS One"},{"key":"B156","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1111\/omi.12061","article-title":"TBX21 Participates in Innate Immune Response by Regulating Toll-Like Receptor 2 Expression in Streptococcus Pneumoniae Infections","volume":"29","author":"Woo","year":"2014","journal-title":"Mol. Oral. Microbiol."},{"key":"B157","doi-asserted-by":"publisher","first-page":"3131","DOI":"10.2174\/138161207782110453","article-title":"Defensin Participation in Innate and Adaptive Immunity","volume":"13","author":"Yang","year":"2007","journal-title":"Curr. Pharm. Des."},{"key":"B158","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.diagmicrobio.2016.02.010","article-title":"Detection of Respiratory Pathogens in Pediatric Acute Otitis Media by PCR and Comparison of Findings in the Middle Ear and Nasopharynx","volume":"85","author":"Yatsyshina","year":"2016","journal-title":"Diagn. Microbiol. Infect. Dis."},{"key":"B159","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1016\/j.ceb.2011.07.001","article-title":"Cadherin-Actin Interactions at Adherens Junctions","volume":"23","author":"Yonemura","year":"2011","journal-title":"Curr. Opin. Cell Biol."},{"key":"B160","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/j.meegid.2015.08.019","article-title":"Otitis Media Induced by Peptidoglycan-Polysaccharide (PGPS) in TLR2-Deficient (Tlr2(-\/-)) Mice for Developing Drug Therapy","volume":"35","author":"Zhang","year":"2015","journal-title":"Infect. Genet. Evol."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2021.764772\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,29]],"date-time":"2021-10-29T06:09:44Z","timestamp":1635487784000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2021.764772\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,29]]},"references-count":160,"alternative-id":["10.3389\/fcimb.2021.764772"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2021.764772","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,29]]},"article-number":"764772"}}