A model of chronic, transmissible Otitis Media in mice (original) (raw)
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Probing Immune-Mediated Clearance of Acute Middle Ear Infection in Mice
Frontiers in Cellular and Infection Microbiology, 2022
Acute otitis media (AOM) is commonly caused by bacterial pathobionts of the nasopharynx that ascend the Eustachian tube to cause disease in the middle ears. To model and study the various complexities of AOM, common human otopathogens are injected directly into the middle ear bullae of rodents or are delivered with viral co-infections which contribute to the access to the middle ears in complex and partially understood ways. Here, we present the novel observation that Bordetella bronchiseptica, a well-characterized respiratory commensal/pathogen of mice, also efficiently ascends their Eustachian tubes to colonize their middle ears, providing a flexible mouse model to study naturally occurring AOM. Mice lacking T and/or B cells failed to resolve infections, highlighting the cooperative role of both in clearing middle ear infection. Adoptively transferred antibodies provided complete protection to the lungs but only partially protected the middle ears, highlighting the differences bet...
Bacterial otitis media: a new non-invasive rat model
Vaccine, 2003
This study describes the development of a physiological rat model for otitis media. The model is based on the assumption that bacteria, intranasally introduced into the nasopharynx, will be transferred into the middle ear cavity during swallowing provided that the ambient air pressure is higher than the middle ear pressure. This model demonstrates that small pressure changes, generated in a pressure cabin under controlled conditions, can be used as driving force for the transfer of bacteria into the middle ear cavity resulting in bilateral otitis media. Because invasive techniques or biochemical agents are not applied, this model is suited to investigate immunological aspects of otitis media, including the effects of vaccination.
Mouse models for human otitis media
Brain Research, 2009
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.
A new model for NTHi middle ear infection in the Junbo mutant mouse
Disease models & mechanisms, 2015
Acute otitis media, inflammation of the middle ear, is the most common bacterial infection in children and as a consequence is the most common reason for antimicrobial prescription to this age group. There is currently no effective vaccine for the principal pathogen involved, non-typeable Haemophilus influenzae (NTHi).The most frequently used and widely accepted experimental animal model of middle ear infection is in chinchillas, but mice and gerbils have also been used. We have established a robust model of middle ear infection by NTHi in the Junbo mouse, a mutant mouse line that spontaneously develops chronic middle ear inflammation under specific pathogen free conditions. The heterozygote Junbo mouse (Jbo/+) bears a mutation in a gene (Evi1, also known as Mecom) that plays a role in host innate immune regulation; pre-existing middle ear inflammation promotes NTHi middle ear infection. A single intranasal inoculation with NTHi produces high rates (up to 90%) of middle ear infectio...
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.
Evaluation of the mouse model for acute otitis media
Hearing Research, 2006
Various animal models have been employed for otitis media research. The mouse has been studied less, in spite of its many advantages. To better understand the suitability of the mouse for studies of otitis media, an evaluation was made of its middle ear inflammatory processes following inoculation with heat-killed Streptococcus pneumoniae (strain 6A), one of the three most common bacteria to cause otitis media in the human. A total of 94 BALB/c mice were injected transtympanically with three concentrations of heat-killed bacteria (10 4 , 10 6 , and 10 9 organisms per ml) and inflammation evaluated with both histologic examination and auditory brainstem response audiometry. Dose-related measures of the time course of inflammation showed it was maximal at 3 days. PBS-injected control mice also demonstrated some degree of middle ear inflammation. Therefore, inflammation measures from PBS injected mice were used as the threshold above which histologic inflammatory changes would be considered a response to bacteria. These quantitative comparisons of bacterial and PBS inoculations revealed the most significant middle ear measures of inflammation were amount of fluid in the middle ear, tympanic membrane thickness, and number of inflammatory cells. The induction of middle ear inflammation in the mouse demonstrated the applicability of this model for investigations of otitis media.
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
Chronic suppurative otitis media (CSOM) is a neglected pediatric disease affecting 330 million worldwide for which no new drugs have been introduced for over a decade. We developed a mouse model with utility in pre-clinical drug evaluation and antimicrobial discovery. Our model used immune-competent mice, tympanic membrane perforation and inoculation with luminescent Pseudomonas aeruginosa that enabled bacterial abundance tracking in real-time for 100 days. The resulting chronic infection exhibited hallmark features of clinical CSOM, including inhibition of tympanic membrane healing and purulent ear discharge. We evaluated the standard care fluoroquinolone ofloxacin and demonstrated that this therapy resulted in a temporary reduction of bacterial burden. These data are consistent with the clinical problem of persistent infection in CSOM and the need for therapeutic outcome measures that assess eradication post-therapeutic endpoint. We conclude that this novel mouse model of CSOM has value in investigating new potential therapies.
Increased secretory capacity of the middle ear mucosa after acute otitis media caused by type B
Otolaryngology - Head and Neck Surgery, 1997
Secretory otitis media is associated with a highly increased goblet cell density of the middle ear mucosa. Previous studies have shown that a single episode of experimental acute otitis media caused by Streptococcus pneumoniae or nontypeable Haemophilus influenzae is followed by increased goblet cell density for a period of at least 6 months. This condition may create a predisposition for subsequent development of secretory otitis media. We inoculated the middle ears of 25 rats with type B H. influenzae to determine the effect of the bacteria on mucosal secretory capacity. Five rats were euthanized 4, 8, 16, 60, and 180 days after inoculation, followed by dissection, staining, and whole-mount embedding of the middle ear mucosa. The goblet cell density was determined in 24 well-defined localities. Compared with that of 25 normal middle ears, the goblet cell density was significantly increased in almost all counting localities on all days of euthanasia. Thus increased goblet cell density and enlargement of mucosal areas containing goblet cells persisted for 6 months after the acute incident. Inoculation of type B H. influenzae induced an increase of goblet cell density that was higher than the increase after inoculation of S. pneumoniae or nontypeable H. influenzae. We conclude that experimental acute otitis media caused by type B H. influenzae is followed by a longstanding increase of mucosal secretory capacity, which is likely to induce a subsequent development of secretory otitis media.
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.