Date Published: April 10, 2019
Publisher: Public Library of Science
Author(s): Kalyan K. Dewan, Dawn L. Taylor-Mulneix, Laura L. Campos, Amanda L. Skarlupka, Shannon M. Wagner, Valerie E. Ryman, Monica C. Gestal, Longhua Ma, Uriel Blas-Machado, Brian T. Faddis, Eric T. Harvill, Dana J. Philpott.
Infection and inflammation of the middle ears that characterizes acute and chronic otitis media (OM), is a major reason for doctor visits and antibiotic prescription, particularly among children. Nasopharyngeal pathogens that are commonly associated with OM in humans do not naturally colonize the middle ears of rodents, and experimental models in most cases involve directly injecting large numbers of human pathogens into the middle ear bullae of rodents, where they induce a short-lived acute inflammation but fail to persist. Here we report that Bordetella pseudohinzii, a respiratory pathogen of mice, naturally, efficiently and rapidly ascends the eustachian tubes to colonize the middle ears, causing acute and chronic histopathological changes with progressive decrease in hearing acuity that closely mimics otitis media in humans. Laboratory mice experimentally inoculated intranasally with very low numbers of bacteria consistently have their middle ears colonized and subsequently transmit the bacterium to cage mates. Taking advantage of the specifically engineered and well characterized immune deficiencies available in mice we conducted experiments to uncover different roles of T and B cells in controlling bacterial numbers in the middle ear during chronic OM. The iconic mouse model provides significant advantages for elucidating aspects of host-pathogen interactions in otitis media that are currently not possible using other animal models. This natural model of otitis media permits the study of transmission between hosts, efficient early colonization of the respiratory tract, ascension of the eustachian tube, as well as colonization, pathogenesis and persistence in the middle ear. It also allows the combination of the powerful tools of mouse molecular immunology and bacterial genetics to determine the mechanistic basis for these important processes.
Acute otitis media (AOM) an inflammation of the middle ear caused by bacterial infections  affects a large portion of the human population every year and is a source of considerable morbidity and societal burden [2, 3]. The majority of those afflicted are infants and children, and the condition is a major reason for antibiotic prescription [4, 5]. The pathogenesis of OM is predominantly attributed to middle ear infections by transmissible pathogens that initially colonize the oro/nasopharynx [6, 7, 8]. Poorly understood mechanisms allow pathogens to ascend the Eustachian tube to reach and colonize the middle ear. Early stages of AOM often induce fever and pain caused by the accumulation of an inflammatory exudate in the middle ear . Increased pressure on the tympanic membrane can affect the auditory ossicles housed in the middle ear resulting in a decrease in the acuity of conductive hearing . AOM is usually a self-resolving condition however, in a subset of patients persistent infections lead to chronic otitis media (COM), a condition accompanied with the risk of more serious complications. Limitations of tractable methods to study OM has severely limited our progress in understanding of the mechanisms used by pathogens to reach the middle ear, or of the host factors [11–14] that determine susceptibility to acute or chronic OM . Therefore, while there has been progress in interventions that alleviate the suffering , the details of host-pathogen interactions during the establishment of acute OM and its progression to a chronic form remain elusive.
Our limited understanding of how pathogens induce AOM in humans is largely based on current experimental approaches that directly inject large doses of human pathogens into the middle ears of rodents inducing a short-lived acute inflammatory response. Any bacterial pathogen delivered in that way is likely to generate some pathology but the relevance to aspects of human disease may be debated. Further, direct inoculation of the middle ear omits critical steps of a natural infection, including early nasopharyngeal colonization and ascension of the Eustachian tube, adherence/colonization of the middle ear, evasion of the innate immune-defenses and subsequent evasion of the adaptive immune response to establish a chronic infection. So, such systems, although they may use important human pathogens, cannot provide insight to any of these critical aspects of the infectious process.