Title: Genetics and Pathobiology of Otitis Media
Funder: Medical Research Council

Abstract: Disease in the middle ear (otitis media) caused by germs (bacteria) is one of the most common reasons why children get ill and visit their doctor. It causes sore ears that affect most children at least once before the age of five. The disease can become prolonged with constant fluid in the ear that leads to problems with hearing and often learning difficulties for the affected children. At MRC Harwell Institute we investigate ear disease and the genes associated with it using the mouse. We study the ears of mice with genetic mutations that make them more likely to get otitis media to discover the mechanisms and physiology underlying the disease and to test better ways to treat the disease. We can infect the middle ear of these mice in much the same way that the germs infect in children. Our studies in the mouse help us to better understand what things are important and combine to cause and prolong this infection, and can give us fresh ideas on how to lessen disease. Our successful mouse models allow us to test new ways that could prevent or treat the equivalent middle ear infection in children. Technical Summary Otitis media (OM), inflammation of the middle ear bulla, is a very common childhood disease. Chronic OM with effusion, otherwise known as glue ear, is the most common cause of hearing impairment in children and can lead to learning difficulties. In the UK, on average, at least one episode of OM occurs in every child by the age of five. OM is often initiated by bacterial infection (acute OM) and is the single most reason for antibiotic prescription in this age group. Non-typeable Haemophilus influenzae (NTHi) is a predominant bacterium associated with acute OM. Our aim is to utilise mouse models to investigate the genetics and pathobiology of OM and discover novel means to reduce the very significant morbidity associated with the disease in human. The group has identified and characterised several mouse models of chronic OM that have enabled fundamental and ground-breaking studies into the genes and immune signalling mechanisms that influence the development and persistence of this predominantly childhood condition. Key genes in the relevant pathways when mutated in the mouse share common pathology to human disease and are the same genes associated with chronic OM in the human population. Genetic, cellular and biochemical analyses have identified the underlying determinants of the disease phenotype in the mouse. Mouse models provide a means to test strategies to diminish OM by targeting the inflamed conditions; VEGF receptor inhibitors have proven to be efficacious in the mouse models in mitigating middle ear inflammation and hearing loss. Chronic OM models are permissive to infection by human otopathogens such as NTHi and enable studies of host microbial interactions that are relevant to the onset, progression and resolution of acute OM. Immunological studies identify host immune cells and signalling pathways that are key to the infection process. OM mouse infection models provide a means to test novel vaccine candidates to prevent acute OM and investigate new therapeutic regimens to more effectively treat the disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EAR