21-ICRAD Virulent Non-Notifiable Avian Influenza; Determinants of virulence of emerging viruses
Lead Research Organisation:
University of Edinburgh
Department Name: The Roslin Institute
Abstract
Europe is one of the world's largest poultry meat and egg producers and exporter of poultry products. Disease outbreaks are a major threat for the poultry industry. Avian Influenza (AI) is listed as a top challenge and with that, is a major concern of the European and worldwide poultry industry. In poultry, the severity of AI virus (AIV) strains is classified into Highly Pathogenic (HPAI) or Low Pathogenic (LPAI). HPAI strains cause severe infections and high levels of mortality. HPAI and LPAI of the H5 and H7 types are notifiable diseases, i.e. diseases that are required by law to be reported to government authorities. The collation of information allows the authorities to monitor the disease, and provides early warning of possible outbreaks. European Member states conduct surveillance programmes and outbreaks involving AI H5 and H7 subtypes are notifiable to the OIE. However, not only LPAI H5 and H7 and HPAI subtypes form a threat for the poultry industry. Several of the non H5/H7 subtypes such as H3 and H9, can be very virulent and infections with these strains can also cause severe production losses. Besides the economic consequences, these virulent non-notifiable LPAI (nn-LPAI) subtypes have a major impact on animal welfare by causing severe clinical symptoms, high mortality rates and - in case of controlling the outbreak - culling of diseased and/or healthy flocks. AI is a zoonotic disease and past influenza pandemics were caused by viruses that were at least partly derived from AI viruses. Therefore, impacts on public health may be great if nn-LPAI with high zoonotic potential are not controlled adequately.
The FluNuance consortium aims to develop a diagnostic tool or identification system for virulent nn-LPAI strains. To achieve this we will first have to understand why these normally low pathogenic viruses become more pathogenic and how they interact with their hosts, chickens and representatives of wildlife: mallard, geese and pigeon. This knowledge will allow us to better assess the potential risks that viruses from the animal reservoir imposes for the poultry industry and vice versa. As a consequence, poultry production will be threatened less by these viruses, thereby reducing negative impacts on animal welfare and decreasing the numbers of flocks that are culled. In case the emerging nn-LPAI has high zoonotic potential, the risk of a pandemic will be lowered. Thus, this proposal addresses the ever-increasing importance of the poultry industry and aligns with the consumers' demands for 'healthy food from healthy animals'.
The FluNuance consortium aims to develop a diagnostic tool or identification system for virulent nn-LPAI strains. To achieve this we will first have to understand why these normally low pathogenic viruses become more pathogenic and how they interact with their hosts, chickens and representatives of wildlife: mallard, geese and pigeon. This knowledge will allow us to better assess the potential risks that viruses from the animal reservoir imposes for the poultry industry and vice versa. As a consequence, poultry production will be threatened less by these viruses, thereby reducing negative impacts on animal welfare and decreasing the numbers of flocks that are culled. In case the emerging nn-LPAI has high zoonotic potential, the risk of a pandemic will be lowered. Thus, this proposal addresses the ever-increasing importance of the poultry industry and aligns with the consumers' demands for 'healthy food from healthy animals'.
Technical Summary
Disease outbreaks are a major threat for the European poultry industry. Avian Influenza A virus (AIV) is a global problem, causing widespread harm to animal and public health, animal welfare and food production. In poultry, pathogenicity of AIV strains is binary classified into Highly Pathogenic (HPAI) and Low Pathogenic (LPAI), using an intravenous pathogenicity index (IVPI) test in 6-week-old chickens and/or the presence of multiple basic amino acids at the cleavage site of the virus hemagglutinin (HA). Many non-notifiable (nn-LPAI; i.e. non H5/H7 subtype) AIV strains usually cause mild or moderate infections, but with highly variable mortality. High virulence nn-LPAIVs are not predicted by IVPI, as shown by recent outbreaks in Belgium, where an H3N1 strain formally classified as LPAI (IVPI = 0.13) nevertheless caused >50% mortality and a 100% drop in egg production.
The FluNuance consortium aims to understand the determinants of increased virulence of LPAI in chickens and representatives of wildlife: mallard,
geese and pigeon, and to extrapolate this to host cell tropism in order to better assess the potential risks that viruses from the animal reservoir imposes for the poultry industry and vice versa. Since these viruses may have a significant impact on animal health and welfare, we will determine the biomarkers and develop tools to predict high virulence of non-H5/H7 viruses.
The FluNuance consortium aims to understand the determinants of increased virulence of LPAI in chickens and representatives of wildlife: mallard,
geese and pigeon, and to extrapolate this to host cell tropism in order to better assess the potential risks that viruses from the animal reservoir imposes for the poultry industry and vice versa. Since these viruses may have a significant impact on animal health and welfare, we will determine the biomarkers and develop tools to predict high virulence of non-H5/H7 viruses.
Description | Low pathogenic avian influenza virus (LPAIV) normaly does not cause major pathology nor mortality in chickens in contrast to high pathogenic avian influenza virus (HPAIV). There are however certain strains of LPAIV that do cause major losses in poultry flocks, for example Ck/Belgium H3N1. This strain has an unusual haemagglutinin cleavage site and we have shown that the unusual cleavage does not confer a pseudo-HPAIV trypsin independent behaviour that enables the virus to replicate throughout the body instead of in limited tissues. A revised hypothesis has been tested and demonstrated the role of plasminogen in neuraminidase (NA)-mediated cleavage of HA which can enhance viral replication and spread as was seen in infected flocks. Additonal in vitro experiments using 3D enteroids are employed to investigate the mechanisms behind the altered cleavage of HA and test mutant viruses to pinpoint which parts of the HA and NA proteins are crucial. These results will be published in 2024. To address the question if chicken 3D enteroids be used as novel tool to assess virulence of moderate LPAI strains we have infected enteroids with low, mild and moderate LAIV (H5N2, H6N1, H9N2, and H3N1) and quantified virus replication and innate immune responses. No significant differences were found in virus replication over a 4 day period nor did replication differed between enteroids derived from layer or broiler birds. In contrast, significant differences were detected in the induction of antiviral immune responses at 1 and 24 hours after infection of the enteroids. |
Exploitation Route | The ultimate aim is to develop novel diagnostic tools however it is too early to know if we can meet this objective. |
Sectors | Agriculture Food and Drink Other |
Description | Defra SAC-ED sub sub group on highly pathogenic avian influenza |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | Defra Scientific Advisory Committee on Emerging and Exotic Diseases (SAC-ED). |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | Discussion meeting on research gaps in avian influenza |
Geographic Reach | National |
Policy Influence Type | Membership of a guideline committee |
Description | Member of SAC-ED HPAI |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | Genetically ENgineered BIOsensors to detect BIological Threats (GENBIOBIT): Influenza A Virus |
Amount | £131,024 (GBP) |
Funding ID | BB/V017365/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 05/2021 |
End | 05/2022 |
Description | Mitigation Fund |
Amount | £7,700 (GBP) |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2023 |
End | 03/2023 |
Description | Understanding animal health threats from emerging H5 high pathogenicity avian influenza viruses |
Amount | £179,866 (GBP) |
Funding ID | BB/X006123/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 04/2022 |
End | 05/2023 |
Title | avian 3D intestinal organoids |
Description | We have developed complex multilobulated 3D chicken enteroids from intestinal embryonic villi and adult crypts. These avian enteroids develop optimally in suspension without the structural support required to produce mammalian enteroids, resulting in an inside-out enteroid conformation with media-facing apical brush borders. Histological and transcriptional analyses show these enteroids comprise of differentiated intestinal epithelial cells bound by cell-cell junctions, and notably, include intr |
Type Of Material | Technology assay or reagent |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | The development of this tools has led to follow up funding: BB/V019899/1 in which the technology is employed to study determinants of virulence or emerging virulent non-notifiable avian influenza viruses. The technology may be developed as diagnostic tool to rapidly asses virulence of viruses and thereby may reduce the number of animals used for IVPI scores. BB/V011286/1 in which the technology is employed to study the effect of innate immune pressure and host jumps on evolution of newly emerg |
URL | https://www.nature.com/articles/s42003-021-01901-z |
Description | Adisseo consortium |
Organisation | Adisseo |
Country | France |
Sector | Private |
PI Contribution | Obtained a Adisseo Research grant |
Collaborator Contribution | We will bring in our avian organoids technology to study the effect of microbiome on immune development of the gut and resilience to avian influenza. |
Impact | Due to long start up time to set up a consortium agreement the project did not start in 20212 but end 2022, no out put yet. Collaboartive project with INRAE France and LMU Germany funded by Adisseo |
Start Year | 2022 |
Description | Collaboration ANSES |
Organisation | French Agency for Food, Environmental and Occupational Health & Safety (ANSES) |
Country | France |
Sector | Public |
PI Contribution | My research team will work in the ANSES laboratories to set up organotypic avian cultures (intestinal organoids) of chicken, turkey and Guinea fowl which will be a unique opportunity. The organoids will then be infected with a variety of coronaviruses and avian influenza viruses (low and high pathogenic) and the viral replication will be analysed at different time points post infection. The RNA will be isolated and transported back to the UK to investigate the species specific immune responses using a high throughput qPCR array. The Roslin team will train the scientist at ANSES how to culture organoids whereas the team at ANSES will train the ECRs in virological techniques and working in a high containment laboratory. |
Collaborator Contribution | The team at ANSES will contribute a lot of staff time, the animals, and will do the infection experiment in their high containment laboratory. In addition they will analyse the virus replication (RT-qPCR, egg titration and plaque assays) and we will write a joined publication describing the outcomes of this collaborative project. The data will feed in to many other projects related to avian corona and avian influenza viruses that are ongoing in the Vervelde group. |
Impact | A collaborative project with ANSES, Ploufragan laboratory (reference lab for avian influenza), was initiated and funded by the BBSRC mitigation fund. This is a multidisciplinary collaboration in which the Roslin ECRs and PI will contribute their expertise in organotypic avian cultures (organoids) and the team at ANSES will contribute their virological expertise, the capacity to work with highly pathogenic avian influenza and their access to poultry species that we do not have in the U.K. (including guinea fowl, SPF turkeys and SPF ducks). The output of this collaboration will be joined peer reviewed publications on on host specific viral entry and immune responses (avian corona viruses and avian influenza viruses), preliminary data for follow on funding and future access to a wealth of virus strains and high containment laboratory and animal facilities. |
Start Year | 2022 |
Description | Flu-MAP |
Organisation | Animal and Plant Health Agency |
Country | United Kingdom |
Sector | Public |
PI Contribution | "Flu-MAP" (formal name "Understanding animal health threats from emerging H5 high pathogenicity avian influenza viruses" and code BB/X006123/1) is a BBSRC/Defra-funded Rapid Response award set up in response to the recent epidemic in Northern Europe of highly pathogenic avian influenza in wild and domestic birds. The aim of the consortium funded by this award is to establish an interdisciplinary consortium with the expertise to provide research-led responses and mitigation to the current crisis. The two UK/University of Edinburgh PIs on the US-UK BBSRC-NIFA collaboration award are part of Flu-MAP involved in supplying broadly the same areas of expertise: molecular influenza virology (Professor Paul Digard, local lead PI) and avian immunology (Professor Lonneke Vervelde). |
Collaborator Contribution | Flu-MAP is led by the APHA (Professor Ian Brown; HPAIV and surveillance expertise) with other partners at The Pirbright Institute (Professor Munir Iqbal; HPAIV molecular virology), The University of Nottingham (Professor Kin-Chow Chang; respiratory RNA viruses), The Royal Veterinary College (Professor Nicola Lewis; epidemiology and modelling), the University of Leeds (Professor Alaistair Ward; ornithology), The University of Cambridge (Professor James Wood; epidemiology) and Imperial College London (Professor Wendy Barclay; molecular influenza virology). |
Impact | Please see separate Researchfish entry for the Flu-MAP consortium |
Start Year | 2022 |
Description | GD animal health Deventer, collaborators on grant BB/M01206911 |
Organisation | GD Animal Health |
Country | Netherlands |
Sector | Private |
PI Contribution | GD Animal Health has performed VN assays for our project In 2021 his longstanding collaboration has resulted in the ICRAD FluNuance consortium, co funded by the BBSRC. |
Collaborator Contribution | provided us with antisera, protocols and virus |
Impact | https://www.icrad.eu/wp-content/uploads/2020/11/54_abstract_FluNuance.pdf Joined ICRAD consortium BB/V019899/1 |
Start Year | 2015 |
Description | Interview with Financial Times over avian influenza |
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 | A filmed interview with a journalist from the FT - the purpose to inform the newspaper's audience on the current outbreak of highly pathogenic avian influenza. |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.youtube.com/watch?v=f-aHbL2mc_c |
Description | Interview with Jeremy Howell of the BBC over avian influenza |
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 | Interview with Jeremy Howell of the BBC over avian influenza - parts ended up in an online BBC article and on YouTube - https://www.youtube.com/watch?v=f-aHbL2mc_c |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.bbc.co.uk/news/science-environment-63464065 |
Description | Interview with the Financial Times over avian influenza |
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 with Anjana Ahuja of the Financial Times over avian influenza. This led to quotes in a written article and a follow-up filming visit. |
Year(s) Of Engagement Activity | 2022 |
URL | https://enterprise-sharing.ft.com/redeem/53cb2981-8411-4a92-9049-9dd62921ca84 |
Description | Interview with the Guardian newspaper over avian influenza |
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 | An interview with several follow up points with Phoebe Weston of the Grauniad newspaper over avian influenza, leading to a quote in one of her articles |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.theguardian.com/environment/2022/jul/20/avian-flu-h5n1-wreaks-devastation-seabirds-aoe |
Description | Media attention after launch project initiated by Prof L Vervelde |
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 | Industry/Business |
Results and Impact | Press release after launch project received a lot of attention https://www.thepoultrysite.com/articles/bird-influenza-tests-being-research-that-can-assess-emerging-strains https://www.farminguk.com/news/new-bird-flu-tests-to-assess-emerging-strains_57986.html https://www.poultrynews.co.uk/news/researchers-target-mutating-avian-influenza-strains-in-new-study.html https://www.pressandjournal.co.uk/fp/business/farming/3050836/scots-scientists-to-develop-new-tissue-tests-to-detect-bird-flu/ https://mrcvs.co.uk/en/news/20367/Scientists-seek-avian-flu-tests-to-assess-emerging-strains https://www.thepoultrysite.com/news/2021/04/researchers-begin-developing-tissue-tests-to-detect-emerging-bird-flu-strains |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.thepoultrysite.com/news/2021/04/researchers-begin-developing-tissue-tests-to-detect-emer... |
Description | Panelist for Science Media Centre media briefing event on avian influenza |
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 | Panelist alongside the UK Chief Veterinary Officer and an Animal & Plant Health Agency representative for a media-briefing press conference on the subject of avian influenza. At least one clip was used on the Radio 4 Today programme (18/10/2022) |
Year(s) Of Engagement Activity | 2022 |
Description | Scoping discussion with ITN Productions over a broadcast on vaccines and avian influenza |
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 | ITN Productions are collaborating with GAVI, the Vaccine Alliance and New Scientist to produce a series of science-based news-style programmes. The first programme is to be on vaccines, timed to coincide with World Immunisation Week. My involvement was a scoping discussion over my or wider Roslin involvement in this, or future episodes. |
Year(s) Of Engagement Activity | 2022 |