Genetics and Pathobiology of Otitis Media

Lead Research Organisation: MRC Mammalian Genetics Unit

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.

Publications

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Bowl MR (2018) Genetic landscape of auditory dysfunction. in Human molecular genetics

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Santos-Cortez RLP (2020) Panel 3: Genomics, precision medicine and targeted therapies. in International journal of pediatric otorhinolaryngology

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Thornton RB (2020) Panel 7 - Pathogenesis of otitis media - a review of the literature between 2015 and 2019. in International journal of pediatric otorhinolaryngology

 
Description Scientific Advisory Board, Czech Centre for Phenogenomics (CCP)
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
 
Description Special Advisor, Australian Phenomics Network
Geographic Reach Australia 
Policy Influence Type Participation in a advisory committee
 
Description UK-China Joint Steering Group - promoting scientific and technological innovation and cooperation in Laboratory Animal Science
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
 
Description AMP treatment of Otitis Media 
Organisation Madam Therapeutics
Country Netherlands 
Sector Private 
PI Contribution This collaboration is utilising the mouse infection model established at MRC Harwell to investigate the treatment of OM with antimicrobial peptides.
Collaborator Contribution Madam Therapeutics supply custom AMPs for the treatment of OM in infection models. The UCL Ear Institute has world renowned clinical expertise in the treatment of OM in man.
Impact none yet
Start Year 2015
 
Description AMP treatment of Otitis Media 
Organisation University College London
Department Ear Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution This collaboration is utilising the mouse infection model established at MRC Harwell to investigate the treatment of OM with antimicrobial peptides.
Collaborator Contribution Madam Therapeutics supply custom AMPs for the treatment of OM in infection models. The UCL Ear Institute has world renowned clinical expertise in the treatment of OM in man.
Impact none yet
Start Year 2015
 
Description C-reactive protein and non-typeable Haemophilus influenzae 
Organisation Research Complex at Harwell
Country United Kingdom 
Sector Public 
PI Contribution We carry out in-vitro and in-vivo analyses of the interaction of C-reactive protein with non-typeable Haemophilus influenzae and its biological consequences.
Collaborator Contribution They carry out high resolution microscopy studies of the binding of C-reactive protein to the bacterial surface in the presence or absence of other immune molecules.
Impact Multi-disciplinary; biology and structural chemistry
Start Year 2018
 
Description Diamond Light Source 
Organisation Diamond Light Source
Country United Kingdom 
Sector Private 
PI Contribution We test the function of wild-type and genetically engineered antimicrobial peptide uptake systems of NTHi in our mouse infection model for otitis media.
Collaborator Contribution They carry out detailed structural analyses of the uptake systems to elucidate the roles of individual components.
Impact None yet
Start Year 2014
 
Description Effect of otitis media on fibrosis and cochlear implants 
Organisation University of Southampton
Country United Kingdom 
Sector Academic/University 
PI Contribution We provide the mouse model to facilitate the investigation of chronic otitis media on cochlear implants.
Collaborator Contribution They have clinical and scientific expertise in the use and function of cochlear implants in human.
Impact none yet
Start Year 2020
 
Description Effect of otitis media on glial cells 
Organisation University of Southampton
Country United Kingdom 
Sector Academic/University 
PI Contribution Our mouse models of chronic otitis media provide a means to test the long term effect of inflammation on the function of glial cells in the inner ear and auditory complex.
Collaborator Contribution our partner has significant expertise in investigating the state and function of glial cells in the auditory pathway.
Impact non yet
Start Year 2018
 
Description Investigation of genetic basis for otitis media in Down Syndrome patients 
Organisation University of Colorado Denver
Country United States 
Sector Academic/University 
PI Contribution Supply of candidate genes from mouse studies that may contribute to OM phenotype in human.
Collaborator Contribution Study of candidate genes responsible for OM in human patients.
Impact none as yet.
Start Year 2019
 
Description Investigation of otitis media in Down Syndrome mice 
Organisation Francis Crick Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Investigation of the genetic basis and pathobiology of otitis media in mice with Down Syndrome.
Collaborator Contribution Supply of Down Syndrome mice.
Impact none as yet
Start Year 2017
 
Description Investigation of otitis media in Down Syndrome mice 
Organisation University College London
Department Institute of Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution Investigation of the genetic basis and pathobiology of otitis media in Down Syndrome mouse models.
Collaborator Contribution Supply of Down Syndrome mice.
Impact none as yet
Start Year 2016
 
Description Investigation of the role of middle ear stem cells in otitis media. 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Supply of mouse models of otitis media to study the role of epithelial stem cells in the disease.
Collaborator Contribution Investigating the role of the epithelial stem cells in the development and maintenance of otitis media.
Impact none as yet
Start Year 2017
 
Description Lung phenotype in OM mouse mutants 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Provide mutant mice with chronic otitis media for study.
Collaborator Contribution Study of lung phenotype of mice with chronic otitis media.
Impact 3 joint publications
Start Year 2006
 
Description Moraxella catarrhalis infection 
Organisation Griffith University
Country Australia 
Sector Academic/University 
PI Contribution We supply the mouse infection models that are used to test and assess Moraxella catarrhalis infection with respect to respiratory diseases.
Collaborator Contribution Supply of Moraxella catarrhalis strains and expertise on the culture and pathogenesis of the bacteria.
Impact no outcome to report as yet.
Start Year 2018
 
Description NTHi virulence 
Organisation University of Navarra
Department Institute of Agrobiotechnology
Country Spain 
Sector Academic/University 
PI Contribution We provide NTHi strains for research and test strains in our mouse infection model
Collaborator Contribution In vitro and in vivo analyses of NTHi virulence and pathogenesis.
Impact several joint scientific publications.
Start Year 2007
 
Description Surfactant proteins 
Organisation Keele University
Country United Kingdom 
Sector Academic/University 
PI Contribution Understanding the role of lipopolysaccharide in the interaction of NTHi with the innate immune proteins SP-A and SP-D.
Collaborator Contribution Crystallisation and structural analyses of the interaction of NTHi lipopolysaccharide with the innate immune proteins SP-A and SP-D and study of the role of these proteins in bacterial clearance in disease and therapy.
Impact The collaboration involves paediatric clinicians specialising in infectious disease, microbiologists, and structural chemists.
Start Year 2006
 
Description Surfactant proteins 
Organisation University of Southampton
Country United Kingdom 
Sector Academic/University 
PI Contribution Understanding the role of lipopolysaccharide in the interaction of NTHi with the innate immune proteins SP-A and SP-D.
Collaborator Contribution Crystallisation and structural analyses of the interaction of NTHi lipopolysaccharide with the innate immune proteins SP-A and SP-D and study of the role of these proteins in bacterial clearance in disease and therapy.
Impact The collaboration involves paediatric clinicians specialising in infectious disease, microbiologists, and structural chemists.
Start Year 2006
 
Description T cells and NTHi disease 
Organisation University of Oxford
Department Nuffield Department of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of NTHi strains and the mouse infection model to study the role of T cells in respiratory tract infection.
Collaborator Contribution Provision of significant expertise relevant to analysing the frequency and function of immune cells in respiratory tract infection in the mouse.
Impact Exchange of bacterial strains and knowledge.
Start Year 2017
 
Description Genomics, precision medicine and targeted therapies. 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Survey of current literature and state of knowledge regarding genomics, precision medicine and targeted therapies with respsect to otitis media.
Year(s) Of Engagement Activity 2019
 
Description MRC Harwell Institute Festival 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact This was an open day at MRC Harwell Institute where members of the general public could attend and learn about the science that is conducted on site. Our group presented some aspects of our research under the theme of 'How hearing works'.
Year(s) Of Engagement Activity 2018
 
Description Pathogenesis of otitis media 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Expert panel reviewed the literature and currnet state of knowledge with respsct to the Pathogenesis of otitis media
Year(s) Of Engagement Activity 2019
 
Description Super Science Saturday at Oxford Natural History Museum 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact This was a public exhibition of science at which we presented our research in the context of 'how hearing works'.
Year(s) Of Engagement Activity 2018
 
Description Super Science Saturday at Oxford Natural History Museum 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact An open public science exhibition for families held at the Oxford Natural History Museum.
Year(s) Of Engagement Activity 2016
 
Description U3A talk on deafness 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact presentation on deafness made to U3A group on a day visit to the MRC Harwell Institute.
Year(s) Of Engagement Activity 2017
 
Description University of Southampton Medical School talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact I presented a summary of our research to investigate the role of NTHi bacteria in acute otitis media using mouse models of infection.
Year(s) Of Engagement Activity 2018