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

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 Eya1 haploinsufficiency, with mouse models affecting Eya1, mimicking many of the defects found in patients. Here, we characterize the onset, consequences, and underlying causes of chronic otitis media in Eya1 heterozygous mice. Cavitation defects were evident in these mice from postnatal day (P)11 onwards, with mesenchyme around the promontory and attic regions of the middle ear space. This mesenchyme was still prominent in adult Eya1 heterozygous mice, while the wild-type littermates had fully aerated ears from P14 onwards. MicroCT analysis highlighted a significantly smaller bulla, confirming the link between bulla size defects and the ability of the mesenchyme to retract successfully. Otitis media was observed from P14, often presenting unilaterally, resulting in hyperplasia of the middle ear mucosa, expansion of secretory cells, defects in the motile cilia, and changes in basal epithelial cell markers. A high incidence of otitis media was identified in older mice but only associated with ears with retained mesenchyme. To understand the impact of the environment, the mouse line was rederived onto a super-clean environment. Cavitation defects were still evident at early stages, but these generally resolved over time, and importantly, no signs of otitis media were observed at 6 weeks. In conclusion, we show that a small bulla size is closely linked to defects in cavitation and the presence of retained mesenchyme. A delay in retraction of the mesenchyme predates the onset of otitis media, making the ears susceptible to its development. Early exposure to OM appears to exacerbate the cavitation defect, with mesenchyme evident in the middle ear throughout the animal’s life. This highlights that permanent damage to the middle ear can arise as a consequence of the early onset of OM.

Role of a novel mouse mutant of the Galnt2tm1Lat/tm1Lat gene in otitis media

“…The mutant mice harboring otitis media were characterized by effusion and capillary expansion. Increased goblet cells and PCNA staining indicated mucosa proliferation ( 21 , 22 ). Effusion originates from the infection and inflammation of the middle ear and is exacerbated by dysfunction of the Eustachian tube and mucociliary impairment ( 23 ).…”

Tracking cell layer contribution during repair of the tympanic membrane

“…Such migration defects could be a direct issue with the neural crest or could be caused by the epithelial layers as excess proliferation could physically obstruct movement of the other layers. Finally, it would be interesting to see how infection, such as otitis media, affects the different layers during healing of a perforation, which should be possible by crossing krt5creER, Wnt1cre or Sox17icre reporter mice to otitis media mouse models ( Fons et al, 2022 ). By understanding the contribution of each cell layer in the healing process it may be possible to generate targeted therapeutics for chronic perforations in the future.…”

A meta-analysis on genetic susceptibility to chronic otitis media

“…In addition, the bio lm is rmly attached to the damaged tissues, such as exposed bone ulcers and ulcerated middle ear mucosa, or attached to ear implants, such as tympanic ventilation tubes, further exacerbating the problem of di cult eradication. Although the existence of bio lm in the middle ear of CSOM patients has been con rmed, its exact role in the pathophysiology of the disease remains to be determined [10]. Cytokines are also involved in the pathogenesis of OM.…”

“…CSOM natural immune response means that after the middle ear mucosa is infected by bacteria, the body's natural immune response mainly recognizes the bacterial infection through the receptors on the cell membrane of the middle ear mucosa and the receptors in the cell, and nally triggers the innate immune response to eliminate pathogens, so as to achieve the purpose of self-defense [10]. Due to the occurrence of natural immune response, CSOM can not only mediate the middle ear epithelium to play the role of anti-pathogen infection, but also cause the in ltration of in ammatory cells, secretion of in ammatory cytokines and other damage to the middle ear mucosa in varying degrees.…”