Innate immune sensing of viral DNA by avian macrophages
Lead Research Organisation:
University of Cambridge
Department Name: Pathology
Abstract
Chickens are a globally important food source and hence require protection from infectious diseases. The poultry industry in the UK alone is responsible for the production of more than one million tonnes of chicken meat and billions of eggs every year for consumption. This vast scale of farming necessitates that we understand which diseases pose a threat to the health of these chickens and how we can counter those threats. The use of vaccines is one a primary method used to help protect chickens from infections such as Newcastle disease, infectious bronchitis, fowlpox and Marek's disease. In order to effectively improve current vaccines or design new ones against emerging and zoonotic infections it is important to understand the fundamental mechanisms by which the chicken immune system works and how it interacts with pathogens. Such studies can lead not only to improvements in vaccine design but also to a greater understanding of immunology and virology as a whole. Indeed, the study of avian immunology and virology has lead to several important advances in both fields. In this study we aim to advance our understanding of how chicken cells detect the presence of DNA in the wrong place inside the cell. Such a mis-localisation can be a sign of infection or damage that triggers an alarm called the innate immune system to send signals into the infected or damaged tissue that something is wrong. This system is critical to fight off infections and to drive vaccination responses so understanding how it works will help in the fight against diseases such as Marek's that affect global chicken populations.
Technical Summary
To mount an effective immune response to infection requires sensing and responding to pathogens in the first infected cells. The pattern recognition receptors (PRRs) that directly sense the presence of foreign DNA inside host cells are critical for mounting a rapid and effective innate immune response to virus infections. Despite being extensively studied in mammalian systems, the PRRs that sense viral DNA are not well defined in chickens and their function in pathogen defence poorly characterised. In this study we aim to identify the PRRs responsible for sensing intracellular DNA and analyse the innate sensing pathways that they trigger. There are two key signalling outputs that result from DNA-PRR stimulation; the activation of interferon regulatory factor (IRF)-dependent type-I interferon (IFN-I) and chemokine transcription and inflammasome-dependent interleukin-1beta (IL-1B) processing and secretion. Our preliminary data indicates that these responses are conserved in chicken macrophages, providing the basis by which we can identify and analyse the contribution of DNA sensing PRRs to these signalling responses. Using a combination of genome editing, PRR stimulation, inhibitor studies and infection with Marek's disease virus (MDV) we will analyse the contribution of these PRRs to anti-viral innate responses. We will carry out experiments in a macrophage cell line and confirm our findings in primary bone-marrow derived macrophages. These data will provide important mechanistic information about how chickens mount an immediate immune response to MDV and other DNA viruses as well as to DNA-containing vaccine vectors.
Planned Impact
In this project we will carry out basic scientific research that will lead to an improved understanding of how DNA drives innate immune responses in chickens.
Our study will further the academic discipline through contributing to the training of researchers skilled in a wide range of techniques. The PDRA and RA will acquire new expertise in immunology and virology research which would be widely applicable in the UK biotech industry as well as contributing to training and teaching other laboratory members. In addition, we will have a number of students in the lab over the course of the grant who will also acquire both specialised and transferable skills. These lab members will improve other transferable skills via presentations and networking opportunities at conferences and writing papers and reports during the course of the grant.
Our findings will be disseminated in open access peer-reviewed journals, presentations at suitable scientific conferences, such as the Cambridge Immunology Forum, a Keystone vaccinology conference and other meetings where appropriate to the obtained experimental results. Additionally we will advertise on-line the key facts from our research on our website which will link to any publications and will notify of BBSRC support. Such information will be provided in lay terms as well as more technically in such that it is suitable for all interested parties.
As an method to improve public engagement BF is a Science/Technology/Engineering and Maths (STEM) Ambassador allowing opportunities to interact with and to present this work to young people. The PDRA and RA will be encouraged to engage in such activities and coached by the applicant where necessary.
Our study will further the academic discipline through contributing to the training of researchers skilled in a wide range of techniques. The PDRA and RA will acquire new expertise in immunology and virology research which would be widely applicable in the UK biotech industry as well as contributing to training and teaching other laboratory members. In addition, we will have a number of students in the lab over the course of the grant who will also acquire both specialised and transferable skills. These lab members will improve other transferable skills via presentations and networking opportunities at conferences and writing papers and reports during the course of the grant.
Our findings will be disseminated in open access peer-reviewed journals, presentations at suitable scientific conferences, such as the Cambridge Immunology Forum, a Keystone vaccinology conference and other meetings where appropriate to the obtained experimental results. Additionally we will advertise on-line the key facts from our research on our website which will link to any publications and will notify of BBSRC support. Such information will be provided in lay terms as well as more technically in such that it is suitable for all interested parties.
As an method to improve public engagement BF is a Science/Technology/Engineering and Maths (STEM) Ambassador allowing opportunities to interact with and to present this work to young people. The PDRA and RA will be encouraged to engage in such activities and coached by the applicant where necessary.
Organisations
Publications
Oliveira M
(2020)
Chicken cGAS Senses Fowlpox Virus Infection and Regulates Macrophage Effector Functions.
in Frontiers in immunology
Ricciardi-Jorge T
(2021)
PKR-mediated Stress Response Enhances Dengue and Zika Virus Replication
Wong L
(2021)
Exploiting Connections for Viral Replication.
Wong LH
(2021)
Exploiting Connections for Viral Replication.
in Frontiers in cell and developmental biology
Aggio JB
(2021)
Vaccinia Virus Infection Inhibits Skin Dendritic Cell Migration to the Draining Lymph Node.
in Journal of immunology (Baltimore, Md. : 1950)
Description | We discovered that the chicken virus, Fowlpox, is detected inside chicken cells by a specific set of sensor called cGAS and that detection of the infection in this way makes cells produce anti-viral molecules. We have now discovered further mechanisms by which Fowlpox virus virus is detected by chicken cells and how the virus tries to defend itself from being infected. We have now defined the function and signalling mechanisms of TLR21 and DNA-PK in chicken cells and how fowlpox virus inhibits DNA-PK. |
Exploitation Route | By understanding how avian viruses are sensed by chicken cells, this information lays a platform for understanding more about anti-viral signalling pathways in chicken cells and more about the ways chicken cells respond to infections. Such information can be used to for more fundamental research and also for reserach into avian vaccine design since Fowlpox is used as a vaccine vector. |
Sectors | Agriculture Food and Drink |
Description | BBC Naked Scientists Radio Show Question and Answer program |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Question and Answer panel session on the BBC Naked Scientists Radio show |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.thenakedscientists.com/podcasts/naked-scientists-podcast/why-do-i-stress-eat |
Description | British Society for Immunology Vaccine awareness stand at Cambridge Science Festival |
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 | As part of a public engagement event at the Department of Pathology for the Cambridge Science Festival I set up and ran a vaccine awareness stand in collaboration with the British Society for Immunology. This event ran for a whole Saturday in March 2019 and more than 800 members of the general public attended. The feedback collected from those leaving the event was unanimously positive. |
Year(s) Of Engagement Activity | 2019 |
Description | British Society for Immunology webinar on Covid vaccines |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Webinar on covid vaccines for healthcare professionals |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.immunology.org/coronavirus/connect-coronavirus-webinars/immunology-covid-19-vaccines-hea... |
Description | British Society of Immunology Invited Speaker |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other audiences |
Results and Impact | A talk on Pattern Recognition Receptor regulation of bacterial infection |
Year(s) Of Engagement Activity | 2019 |
URL | http://www.bsicongress.com/sessionspeakers |
Description | Cambridge Festival talk |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Talk about COVID-19 vaccines to the general public |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.festival.cam.ac.uk/ |
Description | Cambridge Festival vaccine masterclass for school children |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Led a masterclass in vaccinology to A level students interested in studying biological sciences and/or medicine at Cambridge as part of the Cambridge Festival |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.festival.cam.ac.uk/ |
Description | Cambridge Science Festival Panel Discussion |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Presentation and question/answer session on infection |
Year(s) Of Engagement Activity | 2019 |
Description | I'm A Scientist Get Me Out of Here |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Schools |
Results and Impact | Online Q&A about vaccines and generally being a scientist with primary school pupils. Resulted in huge numbers of curious questions from primary school children about viruses, vaccines etc.. |
Year(s) Of Engagement Activity | 2020 |
URL | https://imascientist.org.uk/ |
Description | Interview (5) with BBC 3 counties Radio |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Updates on the current COVID situation |
Year(s) Of Engagement Activity | 2020,2021,2022 |
Description | Interview Naked Scientists Radio show |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | A discussion about how vaccines work for a radio program designed to explain to the wider public audience how vaccines work |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.thenakedscientists.com/articles/interviews/tackling-common-vaccine-questions |
Description | Interview for Vice on Covid vaccines |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Engagement in vaccine hesitancy from public and family |
Year(s) Of Engagement Activity | 2020 |
Description | Interview with BBC World Service for a program on COVID -19 |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | An in depth program on new variants of COVID-19 |
Year(s) Of Engagement Activity | 2021 |
Description | Interview with Sky News TV |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Interview about changes in COVID-19 management practices |
Year(s) Of Engagement Activity | 2022 |
Description | Interviews (3) on BBC round robin with various local radio stations |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | The BBC runs a regular 5-6 slot where you talk as an expert to a number of different radio stations from all over the country. I have been called in on a few occasions to update on different aspects of COVID-19 |
Year(s) Of Engagement Activity | 2020,2021,2022 |
Description | Interviews BBC Radio Cambridgeshire (5) |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Media (as a channel to the public) |
Results and Impact | COVID-19, flu, Vaccines |
Year(s) Of Engagement Activity | 2022,2023 |
Description | Interviews for BBC News, BBC radio 5, BBC Cambridgeshire, LBC radion on COVID vaccines |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Interviews and Q&A sessions about covid vaccines |
Year(s) Of Engagement Activity | 2020 |
Description | Interviews for the BBC News channel (TV) 5 to date |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Interviews on different aspects of dealing with the COVID-19 pandemic |
Year(s) Of Engagement Activity | 2021,2022 |
Description | Interviews with BBC 5 Live (Nicky Campbell phone ins (2); Naga Munchetty (2); Colin Murray (2), Stephen Nolan (2)) |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Interviews on different aspects of COVID-19 including vaccines, vaccine hesitancy, new rules, Omicron and other aspects of the science behind dealing with the virus with a veiw to helping people protect themselves during the pandemic |
Year(s) Of Engagement Activity | 2021,2022 |
Description | Interviews with BBC Radio stations (Radio 5 live Stephen Nolan, Nicky Campbell) |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Interview and radio phone in on COVID-19, flu and vaccines |
Year(s) Of Engagement Activity | 2022,2023 |
Description | Interviews with Radio 4 (Womens Hour, The Today program) |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Discussions on Omicron, vaccines and fighting COVID-19 to help people protect themselves against the virus |
Year(s) Of Engagement Activity | 2021,2022 |
Description | Invited Talk University of Birmingham |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other audiences |
Results and Impact | Bacterial Infection Regulation by Pattern Recognition Receptors |
Year(s) Of Engagement Activity | 2019 |
Description | Invited speaker at Imperial College London |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Other audiences |
Results and Impact | Talk about innate immune sensing of influenza |
Year(s) Of Engagement Activity | 2019 |
Description | Invited speaker at the Pirbright Institute |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Other audiences |
Results and Impact | Talk about innate immune sensing of viruses by chickens |
Year(s) Of Engagement Activity | 2019 |
Description | Radio interview BBC Naked Scientists COVID-19 immunology |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Radio interview on the immune response to COVID-19 |
Year(s) Of Engagement Activity | 2020 |
Description | Radio interview BBC Naked Scientists Show on Long COVID |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Discussion of the emergence of long COVID as a clinical condition |
Year(s) Of Engagement Activity | 2020 |
Description | Radio interview BBC Naked Scientists show COVID vaccines |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Radio interview on vaccine approaches for COVID-19 |
Year(s) Of Engagement Activity | 2020 |
Description | Radio interview BBC Radio Cambridgeshire on COVID-19 variants, long COVID and vaccine escape |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Radio interview Q and A on COVID-19 variants, long COVID and vaccine escape |
Year(s) Of Engagement Activity | 2021 |
Description | Regular Interviews (biweekly) with BBC Radio Cambridgeshire on current COVID status |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Over the 12 months of this reporting period I have regular appeared (every 2 weeks) on BBC Radio Cambridgeshire to discuss the impact of COVID and explain the guidelines to help people understand how best to protect themselves and others in the local community |
Year(s) Of Engagement Activity | 2020,2021,2022 |
Description | Science Media Centre expert activity |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Provided comments, quotes and interviews for the Science Media Centre around COVID vaccine policy and immunology. Led to being quoted in numerous national newspapers (FT, Times, Sun, Guardian etc..) and requests from national journalists for further information and commentry. |
Year(s) Of Engagement Activity | 2021,2022 |
URL | https://www.sciencemediacentre.org/ |
Description | Science Media Centre expert activity |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Commentary on significant findings as part of a panel of experts reporting to the Science Media Centre, leading to published comments on specific COVID19-related findings and interviews with journalists around vaccination, ultimately to comments or contributions to national and international press publications (The Sun, Financial Times, Vice.com etc) or media broadcast interviews on radio and television (BBC News, BBC Radio 5 Live, BBC radio Cambs, LBC etc..) |
Year(s) Of Engagement Activity | 2020,2021 |
URL | https://www.sciencemediacentre.org/ |
Description | Talk at Cambridge Festival (x2) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | I ran a Cambridge Festival session on "WHY DO BUGS JUMP FROM ANIMALS TO PEOPLE- THE BILLION DOLLAR QUESTION" which was attended by 50-100 people. There was a 30 minute question session where we answered questions from the general public. I talked at a second Cambridge Festival session entitled "MONKEYPOX: LESSONS FROM VIROLOGY AND FROM HISTORY" which was to an audience of 30 people from the general public and, again, there was a good question session lasting about 20 minutes. |
Year(s) Of Engagement Activity | 2023 |
URL | https://www.eventbrite.co.uk/e/monkeypox-lessons-from-virology-and-from-history-tickets-545991373897 |
Description | Talk at Cambridge Science Fair |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | I gave a talk and chaired a question and answer session on the detection of pathogens by the immune system |
Year(s) Of Engagement Activity | 2022 |
Description | Talk at Cambridge Science Fair |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Talk and panel discussion at the Cambridge Festival |
Year(s) Of Engagement Activity | 2022 |
Description | Talk at University of Indianapolis |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Talk on evolution of innate immunity and its relevance to zoonotic infections |
Year(s) Of Engagement Activity | 2022 |
Description | Talk for Royal College of Surgeons Ireland |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | A talk on Pattern Recognition Receptors in Infectious and Inflammatory disease |
Year(s) Of Engagement Activity | 2022 |