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Article ; Online: Mouse models for human otitis media.

Trune, Dennis R / Zheng, Qing Yin

2009 Volume 1277, Page(s) 90–103

Abstract: ... numbers of mouse models are helping to uncover the potential genetic bases for human OM. Furthermore ... status, genetic predisposition, and environment. Recent progress in mouse model development is helping ... Otitis media (OM) remains the most common childhood disease and its annual costs exceed $5 billion ...

Abstract	Otitis media (OM) remains the most common childhood disease and its annual costs exceed $5 billion. Its potential for permanent hearing impairment also emphasizes the need to better understand and manage this disease. The pathogenesis of OM is multifactorial and includes infectious pathogens, anatomy, immunologic status, genetic predisposition, and environment. Recent progress in mouse model development is helping to elucidate the respective roles of these factors and to significantly contribute toward efforts of OM prevention and control. Genetic predisposition is recognized as an important factor in OM and increasing numbers of mouse models are helping to uncover the potential genetic bases for human OM. Furthermore, the completion of the mouse genome sequence has offered a powerful set of tools for investigating gene function and is generating a rich resource of mouse mutants for studying the genetic factors underlying OM.
MeSH term(s)	Animals ; Disease Models, Animal ; Humans ; Immunotherapy, Active ; Mice ; Otitis Media/genetics ; Otitis Media/immunology ; Otitis Media/microbiology ; Otitis Media/therapy ; Toll-Like Receptors/metabolism
Chemical Substances	Toll-Like Receptors
Language	English
Publishing date	2009-03-06
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/j.brainres.2009.02.047
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Article: Resolution of otitis media in a humanized mouse model.

Son, Ye Lin / Pak, Kwang / Muradagha, Nada / Heo, Kyung Wook / Leichtle, Anke / Kurabi, Arwa

Frontiers in genetics

2022 Volume 13, Page(s) 958540

Abstract: Otitis media (OM) is one of the largest public health problems of children and has devastating ... to study the human immune system in an animal model. Here we describe the first use of humanized mice ... impacts in developing countries. The substantial medical and human costs involved have led to research ...

Abstract	Otitis media (OM) is one of the largest public health problems of children and has devastating impacts in developing countries. The substantial medical and human costs involved have led to research to understand the disease and improve treatment. Animal models of OM have yielded critical information about the immune, inflammatory and genetic mechanisms of OM. However, it is important to link animal studies to human immune and inflammatory responses. In recent years, "humanized" mice have become a valuable tool to study the human immune system in an animal model. Here we describe the first use of humanized mice to study OM. We demonstrate that humanized mice with a sufficient degree of engraftment recapitulate a normal middle ear (ME) inflammatory response to bacterial infection, including the recruitment of human immune cells, and exhibit normal recovery. Moreover, these animals exhibit regulated expression of human-specific immune and inflammatory genes in the ME. In contrast, mice with insufficient engraftment fail to resolve OM. This model has many potential uses in OM research, including using hematopoietic stem cells from patients with differing degrees of OM susceptibility, to understand the role of human immune responses in proneness to this common childhood disease.
Language	English
Publishing date	2022-11-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2022.958540
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Article ; Online: An infant mouse model of influenza-driven nontypeable

Landwehr, Katherine R / Granland, Caitlyn M / Martinovich, Kelly M / Scott, Naomi M / Seppanen, Elke J / Berry, Luke / Strickland, Deborah / Fulurija, Alma / Richmond, Peter C / Kirkham, Lea-Ann S

Infection and immunity

2024 Volume 92, Issue 5, Page(s) e0045323

Abstract: ... ...

Abstract	Nontypeable
MeSH term(s)	Animals ; Otitis Media/microbiology ; Haemophilus influenzae/growth & development ; Haemophilus influenzae/pathogenicity ; Haemophilus influenzae/physiology ; Haemophilus Infections/microbiology ; Disease Models, Animal ; Mice ; Influenza A virus/pathogenicity ; Influenza A virus/growth & development ; Mice, Inbred BALB C ; Orthomyxoviridae Infections/virology ; Orthomyxoviridae Infections/complications ; Humans ; Animals, Newborn
Language	English
Publishing date	2024-04-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218698-6
ISSN	1098-5522 ; 0019-9567
ISSN (online)	1098-5522
ISSN	0019-9567
DOI	10.1128/iai.00453-23
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Zs.A 684: Show issues

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Article ; Online: The A2ml1-Knockout mouse as an animal model for non-syndromic otitis media.

Elling, Christina L / Gomez, Helen Z / Lee, Nam K / Hirsch, Scott D / Santos-Cortez, Regie Lyn P

International journal of pediatric otorhinolaryngology

2024 Volume 181, Page(s) 111980

Abstract: ... mouse models for OM rely on inducing acute infection through inoculation of the middle ear, e.g ... with the human otopathogen non-typeable Haemophilus influenzae (NTHi), and with very few genetic models ... Background: Inflammation and infection of the middle ear, known as otitis media (OM), is a leading ...

Abstract	Background: Inflammation and infection of the middle ear, known as otitis media (OM), is a leading cause of hearing loss and the most frequently diagnosed disease in children worldwide. Traditionally, mouse models for OM rely on inducing acute infection through inoculation of the middle ear, e.g. with the human otopathogen non-typeable Haemophilus influenzae (NTHi), and with very few genetic models with spontaneous or chronic OM. A2ML1 variants, including loss-of-function variants, were associated with susceptibility to OM in humans, but no animal model has been reported for A2ml1-related OM. Here, we report our middle ear findings in a mouse line with a CRISPR-induced knockout (KO) of A2ml1. Methods: Mice were X-rayed prior to harvest to determine if there are craniofacial or skeletal abnormalities. Tissue from mouse middle ears, as well as other upper respiratory mucosal tissues, were harvested. The harvested middle ear bullae were examined under microscope and submitted for histologic preparation to study phenotypic indications of OM. RNA samples isolated from middle ear tissue were assayed for expression of genes correlated with A2ML1 expression in humans. Results: Data from a total of 119 mice (35 wildtype, 40 heterozygous, 44 homozygous) are presented here, with each analyses being performed on subsets of these mice. There were no significant craniofacial differences by genotype (n = 22). Findings in mice with the A2ml1-KO indicated an increased incidence of OM (n=29; odds ratio = 11; CI: 1.1, 573.6; Fisher exact two-sided p = 0.02) with tympanic membrane perforations or thickening, as well as cases of middle ear effusion, inflammatory cells, or fluid from histologic sections. Dsp was upregulated in the middle ear tissues of homozygous mice (Wilcoxon test p = 0.001). Conclusion: Thus far, our results in this A2ml1-KO mouse line indicate spontaneous occurrence of OM and dysregulation of Dsp in the middle ear as a potential disease mechanism for A2ml1-related OM.
Language	English
Publishing date	2024-05-10
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	754501-0
ISSN	1872-8464 ; 0165-5876
ISSN (online)	1872-8464
ISSN	0165-5876
DOI	10.1016/j.ijporl.2024.111980
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Zs.A 1507: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Mouse models as a tool to unravel the genetic basis for human otitis media.

Zheng, Qing Yin / Hardisty-Hughes, Rachel / Brown, Steve D M

Brain research

2006 Volume 1091, Issue 1, Page(s) 9–15

Abstract: ... mouse models to uncover the genetic basis for human OM. ... underlying OM. We review the literature and discuss recent progresses in developing mouse models and using ... The pathogenesis of otitis media (OM) is multifactorial and includes infection, anatomical ...

Abstract	The pathogenesis of otitis media (OM) is multifactorial and includes infection, anatomical factors, immunologic status, genetic predisposition, and environmental factors. OM remains the most common cause of hearing impairment in childhood. Genetic predisposition is increasingly recognized as an important factor. The completion of the mouse genome sequence has offered a powerful basket of tools for investigating gene function and can expect to generate a rich resource of mouse mutants for the elucidation of genetic factors underlying OM. We review the literature and discuss recent progresses in developing mouse models and using mouse models to uncover the genetic basis for human OM.
MeSH term(s)	Animals ; Disease Models, Animal ; Humans ; Otitis Media/etiology ; Otitis Media/genetics
Language	English
Publishing date	2006-08-18
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/j.brainres.2006.01.046
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Zs.A 161: Show issues

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Article ; Online: Pathological features in the LmnaDhe/+ mutant mouse provide a novel model of human otitis media and laminopathies.

Zhang, Yan / Yu, Heping / Xu, Min / Han, Fengchan / Tian, Cong / Kim, Suejin / Fredman, Elisha / Zhang, Jin / Benedict-Alderfer, Cindy / Zheng, Qing Yin

The American journal of pathology

2012 Volume 181, Issue 3, Page(s) 761–774

Abstract: ... mouse provides a novel model of human OM and laminopathy. ... Genetic predisposition is recognized as an important pathogenetic factor in otitis media (OM) and ... exhibit early-onset, profound hearing deficits and other pathological features mimicking human laminopathy ...

Abstract	Genetic predisposition is recognized as an important pathogenetic factor in otitis media (OM) and associated diseases. Mutant Lmna mice heterozygous for the disheveled hair and ears allele (Lmna(Dhe/+)) exhibit early-onset, profound hearing deficits and other pathological features mimicking human laminopathy associated with the LMNA mutation. We assessed the effects of the Lmna(Dhe/+) mutation on development of OM and pathological abnormalities characteristic of laminopathy. Malformation and abnormal positioning of the eustachian tube, accompanied by OM, were observed in all of the Lmna(Dhe/+) mice (100% penetrance) as early as postnatal day P12. Scanning electronic microscopy revealed ultrastructural damage to the cilia in middle ears that exhibited OM. Hearing assessment revealed significant hearing loss, paralleling that in human OM. Expression of NF-κB, TNF-α, and TGF-β, which correlated with inflammation and/or bony development, was up-regulated in the ears or in the peritoneal macrophages of Lmna(Dhe/+) mice. Rugous, disintegrative, and enlarged nuclear morphology of peritoneal macrophages and hyperphosphatemia were found in Lmna(Dhe/+) mutant mice. Taken together, these features resemble the pathology of human laminopathies, possibly revealing some profound pathology, beyond OM, associated with the mutation. The Lmna(Dhe/+) mutant mouse provides a novel model of human OM and laminopathy.
MeSH term(s)	Acoustic Impedance Tests ; Animals ; Calcium/blood ; Cell Count ; Cell Movement ; Cilia/pathology ; Cilia/ultrastructure ; Cytokines/genetics ; Cytokines/metabolism ; Disease Models, Animal ; Ear, Middle/abnormalities ; Ear, Middle/pathology ; Ear, Middle/physiopathology ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Epithelial Cells/ultrastructure ; Eustachian Tube/abnormalities ; Eustachian Tube/pathology ; Evoked Potentials, Auditory, Brain Stem/physiology ; Gene Expression Regulation ; Humans ; Inflammation Mediators/metabolism ; Ions/blood ; Lamin Type A/metabolism ; Macrophages, Peritoneal/metabolism ; Macrophages, Peritoneal/pathology ; Mice ; Mice, Mutant Strains ; Otitis Media/blood ; Otitis Media/pathology ; Otitis Media/physiopathology ; Otoacoustic Emissions, Spontaneous/physiology ; Phosphorus/blood ; Time Factors ; Transforming Growth Factor beta/genetics ; Transforming Growth Factor beta/metabolism ; Tumor Necrosis Factor-alpha/genetics ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	Cytokines ; Inflammation Mediators ; Ions ; Lamin Type A ; Lmna protein, mouse ; Transforming Growth Factor beta ; Tumor Necrosis Factor-alpha ; Phosphorus (27YLU75U4W) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2012-07-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/j.ajpath.2012.05.031
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Article ; Online: Auditory function in the Tc1 mouse model of down syndrome suggests a limited region of human chromosome 21 involved in otitis media.

Kuhn, Stephanie / Ingham, Neil / Pearson, Selina / Gribble, Susan M / Clayton, Stephen / Steel, Karen P / Marcotti, Walter

PloS one

2012 Volume 7, Issue 2, Page(s) e31433

Abstract: ... problems in humans, including frequent otitis media. The Tc1 mouse carries a significant part ... to that observed in the Ts65Dn model of Down syndrome which shows otitis media. Genes that are trisomic in Ts65Dn ... of human chromosome 21 (Hsa21) in addition to the full set of mouse chromosomes and shares many phenotypes observed ...

Abstract	Down syndrome is one of the most common congenital disorders leading to a wide range of health problems in humans, including frequent otitis media. The Tc1 mouse carries a significant part of human chromosome 21 (Hsa21) in addition to the full set of mouse chromosomes and shares many phenotypes observed in humans affected by Down syndrome with trisomy of chromosome 21. However, it is unknown whether Tc1 mice exhibit a hearing phenotype and might thus represent a good model for understanding the hearing loss that is common in Down syndrome. In this study we carried out a structural and functional assessment of hearing in Tc1 mice. Auditory brainstem response (ABR) measurements in Tc1 mice showed normal thresholds compared to littermate controls and ABR waveform latencies and amplitudes were equivalent to controls. The gross anatomy of the middle and inner ears was also similar between Tc1 and control mice. The physiological properties of cochlear sensory receptors (inner and outer hair cells: IHCs and OHCs) were investigated using single-cell patch clamp recordings from the acutely dissected cochleae. Adult Tc1 IHCs exhibited normal resting membrane potentials and expressed all K(+) currents characteristic of control hair cells. However, the size of the large conductance (BK) Ca(2+) activated K(+) current (I(K,f)), which enables rapid voltage responses essential for accurate sound encoding, was increased in Tc1 IHCs. All physiological properties investigated in OHCs were indistinguishable between the two genotypes. The normal functional hearing and the gross structural anatomy of the middle and inner ears in the Tc1 mouse contrast to that observed in the Ts65Dn model of Down syndrome which shows otitis media. Genes that are trisomic in Ts65Dn but disomic in Tc1 may predispose to otitis media when an additional copy is active.
MeSH term(s)	Animals ; Chromosomes, Human, Pair 21/physiology ; Cochlea ; Disease Models, Animal ; Down Syndrome/complications ; Down Syndrome/genetics ; Down Syndrome/physiopathology ; Evoked Potentials, Auditory, Brain Stem ; Hair Cells, Auditory ; Hearing ; Humans ; Mice ; Mice, Transgenic ; Neoplasm Proteins ; Otitis Media/etiology
Chemical Substances	Neoplasm Proteins ; Tcim protein, mouse
Language	English
Publishing date	2012-02-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0031433
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Article ; Online: Auditory function in the Tc1 mouse model of down syndrome suggests a limited region of human chromosome 21 involved in otitis media.

Stephanie Kuhn / Neil Ingham / Selina Pearson / Susan M Gribble / Stephen Clayton / Karen P Steel / Walter Marcotti

PLoS ONE, Vol 7, Iss 2, p e

2012 Volume 31433

Abstract	Down syndrome is one of the most common congenital disorders leading to a wide range of health problems in humans, including frequent otitis media. The Tc1 mouse carries a significant part of human chromosome 21 (Hsa21) in addition to the full set of mouse chromosomes and shares many phenotypes observed in humans affected by Down syndrome with trisomy of chromosome 21. However, it is unknown whether Tc1 mice exhibit a hearing phenotype and might thus represent a good model for understanding the hearing loss that is common in Down syndrome. In this study we carried out a structural and functional assessment of hearing in Tc1 mice. Auditory brainstem response (ABR) measurements in Tc1 mice showed normal thresholds compared to littermate controls and ABR waveform latencies and amplitudes were equivalent to controls. The gross anatomy of the middle and inner ears was also similar between Tc1 and control mice. The physiological properties of cochlear sensory receptors (inner and outer hair cells: IHCs and OHCs) were investigated using single-cell patch clamp recordings from the acutely dissected cochleae. Adult Tc1 IHCs exhibited normal resting membrane potentials and expressed all K(+) currents characteristic of control hair cells. However, the size of the large conductance (BK) Ca(2+) activated K(+) current (I(K,f)), which enables rapid voltage responses essential for accurate sound encoding, was increased in Tc1 IHCs. All physiological properties investigated in OHCs were indistinguishable between the two genotypes. The normal functional hearing and the gross structural anatomy of the middle and inner ears in the Tc1 mouse contrast to that observed in the Ts65Dn model of Down syndrome which shows otitis media. Genes that are trisomic in Ts65Dn but disomic in Tc1 may predispose to otitis media when an additional copy is active.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2012-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: The interconnected relationships between middle ear bulla size, cavitation defects, and chronic otitis media revealed in a syndromic mouse model.

Fons, Juan M / Milmoe, Natalie J / Dack, Michael R G / Joshi, Leena / Thompson, Hannah / Tucker, Abigail S

Frontiers in genetics

2022 Volume 13, Page(s) 933416

Abstract: High incidence of chronic otitis media is associated with human craniofacial syndromes, suggesting ... in the ear leading to both sensorineural and conductive hearing loss, including otitis media. 40% of BOR ...

Abstract	High incidence of chronic otitis media is associated with human craniofacial syndromes, suggesting that defects in the formation of the middle ear and associated structures can have a knock-on effect on the susceptibility to middle ear inflammation. Patients with branchio-oto-renal (BOR) syndrome have several defects in the ear leading to both sensorineural and conductive hearing loss, including otitis media. 40% of BOR syndrome cases are due to
Language	English
Publishing date	2022-10-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2022.933416
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Article ; Online: Treatment with a neutrophil elastase inhibitor and ofloxacin reduces P. aeruginosa burden in a mouse model of chronic suppurative otitis media.

Khomtchouk, K M / Joseph, L I / Khomtchouk, B B / Kouhi, A / Massa, S / Xia, A / Koliesnik, I / Pletzer, D / Bollyky, P L / Santa Maria, P L

NPJ biofilms and microbiomes

2021 Volume 7, Issue 1, Page(s) 31

Abstract: ... post-infection in a mouse model of CSOM and in human subjects with the disease. Using multiparameter ... Chronic suppurative otitis media (CSOM) is a widespread, debilitating problem with poorly ... of mature neutrophils, as the most informative factor of host response driving disease in the CSOM mouse ...

Abstract	Chronic suppurative otitis media (CSOM) is a widespread, debilitating problem with poorly understood immunology. Here, we assess the host response to middle ear infection over the course of a month post-infection in a mouse model of CSOM and in human subjects with the disease. Using multiparameter flow cytometry and a binomial generalized linear machine learning model, we identified Ly6G, a surface marker of mature neutrophils, as the most informative factor of host response driving disease in the CSOM mouse model. Consistent with this, neutrophils were the most abundant cell type in infected mice and Ly6G expression tracked with the course of infection. Moreover, neutrophil-specific immunomodulatory treatment using the neutrophil elastase inhibitor GW 311616A significantly reduces bacterial burden relative to ofloxacin-only treated animals in this model. The levels of dsDNA in middle ear effusion samples are elevated in both humans and mice with CSOM and decreased during treatment, suggesting that dsDNA may serve as a molecular biomarker of treatment response. Together these data strongly implicate neutrophils in the ineffective immune response to P. aeruginosa infection in CSOM and suggest that immunomodulatory strategies may benefit drug-tolerant infections for chronic biofilm-mediated disease.
MeSH term(s)	Animals ; Antigens, Ly/metabolism ; Disease Models, Animal ; Drug Synergism ; Female ; Flow Cytometry ; Humans ; Machine Learning ; Male ; Mice ; Neutrophils/immunology ; Ofloxacin/administration & dosage ; Ofloxacin/pharmacology ; Otitis Media, Suppurative/drug therapy ; Otitis Media, Suppurative/immunology ; Otitis Media, Suppurative/microbiology ; Piperidines/administration & dosage ; Piperidines/pharmacology ; Proteinase Inhibitory Proteins, Secretory/administration & dosage ; Proteinase Inhibitory Proteins, Secretory/pharmacology ; Pseudomonas Infections/complications ; Pseudomonas Infections/drug therapy ; Pseudomonas Infections/immunology ; Pseudomonas aeruginosa/drug effects
Chemical Substances	Antigens, Ly ; GW 311616 ; Ly6G antigen, mouse ; Piperidines ; Proteinase Inhibitory Proteins, Secretory ; Ofloxacin (A4P49JAZ9H)
Language	English
Publishing date	2021-04-06
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2817021-0
ISSN	2055-5008 ; 2055-5008
ISSN (online)	2055-5008
ISSN	2055-5008
DOI	10.1038/s41522-021-00200-z
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