A model of chronic, transmissible Otitis Media in mice

Abstract

Infection and inflammation of the middle ears that characterizes acute and chronic o titis m edia (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.

Airway Microbiota-Host Interactions Regulate Secretory Leukocyte Protease Inhibitor Levels and Influence Allergic Airway Inflammation

“…Despite this persistent colonization, we did not observe significant weight loss in Bph -colonized mice compared to control mice over a 3-month period ( Figure S1A ), nor observe sneezing ( Clark et al, 2016 ; Hayashimoto et al, 2012 ), tachypnea, poor grooming, or decreased activity. Consistent with earlier descriptions of Bph mouse colonization and the lack of virulence factors found in classical bordetellae, these results indicated that Bph colonization was persistent and associated with a mild phenotype ( Clark et al, 2016 ; Dewan et al, 2019 ; Ivanov et al, 2016 ; Perniss et al, 2018 ).…”

“…To further investigate the importance of an adaptive immune response in controlling bacterial abundance in the airways, we colonized WT and RAG1 −/− C57BL/6J mice with Bph for 14 days and then sacrificed mice to assess the numbers of bacteria within bronchoalveolar lavage (BAL) fluid. We found that there was significantly greater Bph in the BALs of RAG1 −/− than that of WT mice ( Dewan et al, 2019 ), implicating an adaptive immune response in controlling the degree of bacterial colonization ( Figure 3C ). Interestingly, RAG1 −/− mice colonized for 1 month with Bph did not demonstrate overt pneumonia (e.g., alveolar infiltrates) by histology ( Figure S3A ), nor significant weight loss compared to control mice that received a HK inoculum ( Figure S3B ), indicating that although an adaptive immune response helped control bacterial numbers, innate immune mechanisms were sufficient to prevent lethality.…”

“…Here, we describe the host response to Bordetella pseudohinzii ( Bph ), a recently described murine respiratory microbe ( Clark et al, 2016 ; Ivanov et al, 2016 ) that is also found in wild rodents ( Loong et al, 2018 ), and its effects on a model of AAI. Although Bph persists in the respiratory tract of mice for months after inoculation ( Dewan et al, 2019 ), the preponderance of infections do not lead to overt signs of illness ( Hayashimoto et al, 2012 ). Others have reported that despite its apparent benign effects on mice, Bph can induce changes in pulmonary immune parameters (e.g., neutrophilia), leading to concerns about Bph possibly confounding murine pulmonary disease models ( Clark et al, 2016 , 2017 ; Perniss et al, 2018 ).…”

Conservation of Ancient Genetic Pathways for Intracellular Persistence Among Animal Pathogenic Bordetellae

“…Of these, B. avium and B. hinzii cause respiratory infections in poultry and wild birds (Kersters et al, 1984;Vandamme et al, 1995). B. pseudohinzii was identified as a pathobiont in several mouse breeding colonies (Ivanov et al, 2015(Ivanov et al, , 2016 and was recently shown to cause chronic ear infection in mice (Dewan et al, 2019). B. trematum is an opportunistic human pathogen that can cause severe skin disease and chronic otitis media (Vandamme et al, 1996).…”

Evolution and Conservation of Bordetella Intracellular Survival in Eukaryotic Host Cells

“…The other “avian” species, Bordetella hinzii , colonizes the respiratory tracts of poultry and was shown to cause disease during experimental infection in turkeys ( Vandamme et al, 1995 ; Register and Kunkle, 2009 ), and has also been isolated from immunocompromised humans with respiratory disease and septicemia ( Cookson et al, 1994 ; Funke et al, 1996 ). The closely related Bordetella pseudohinzii , identified as a pathobiont in mouse breeding colonies of commercial vendors ( Ivanov et al, 2015 , 2016 ), was found to cause chronic, transmissible otitis media in mice ( Dewan et al, 2019 ). Bordetella trematum , an opportunistic human pathogen, can cause severe skin disease and chronic otitis media ( Vandamme et al, 1996 ).…”