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.
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.
Organisations
- MRC Mammalian Genetics Unit, United Kingdom (Lead Research Organisation)
- University of Southampton, United Kingdom (Collaboration)
- University of Oxford, United Kingdom (Collaboration)
- University College London, United Kingdom (Collaboration)
- Griffith University (Collaboration)
- University of Navarra, Spain (Collaboration)
- Madam Therapeutics (Collaboration)
- University of Colorado (Denver) (Collaboration)
- Research Complex at Harwell (Collaboration)
- Francis Crick Institute (Collaboration)
- Diamond Light Source, United Kingdom (Collaboration)
- Keele University, United Kingdom (Collaboration)
Publications

Bhutta MF
(2019)
Transcript Analysis Reveals a Hypoxic Inflammatory Environment in Human Chronic Otitis Media With Effusion.
in Frontiers in genetics

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

Ferris MT
(2018)
Host genetic regulation of immune-based and infectious diseases : Introduction to mammalian genome special issue: genetics of infectious disease.
in Mammalian genome : official journal of the International Mammalian Genome Society

Kubinyecz O
(2020)
The Jeff Mouse Mutant Model for Chronic Otitis Media Manifests Gain-of-Function as Well as Loss-of-Function Effects.
in Frontiers in genetics


Mulay A
(2018)
Loss of the homeostatic protein BPIFA1, leads to exacerbation of otitis media severity in the Junbo mouse model.
in Scientific reports

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

Thofte O
(2019)
Anti-EF-Tu IgG titers increase with age and may contribute to protection against the respiratory pathogen Haemophilus influenzae
in European Journal of Immunology

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

Vikhe P
(2018)
Cellular content plays a crucial role in Non-typeable Haemophilus influenzae infection of preinflamed Junbo mouse middle ear
in Cellular Microbiology
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 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 | 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 | 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 |