Virus transmission dynamics and the immune response of birds to avian influenza

Lead Research Organisation: Animal Health & Veterinary Lab Agency
Department Name: Statutory and Exotic Viral Diseases

Abstract

The global spread of H5N1 highly pathogenic avian influenza viruses and their ability to infect not only birds but humans emphasises that human and animal health are unavoidably linked. At present avian influenza remains an animal disease problem under urgent need for control but control in birds will also reduce the potential for a human influenza pandemic. Our knowledge of the behaviour of avian influenza viruses in domestic fowl and wild birds is limited. This proposal poses some fundamental questions that address how the easily the virus can infect chickens, turkeys and ducks; how much, and for how long, virus is shed following infection in each species; and how avian influenza virus infection is controlled by the immune response of birds. Fundamental studies of this type will be critical to the design and implementation of control measures in the short term and the long term.

Technical Summary

At present H5N1 avian influenza is an animal disease problem under urgent need of control. The widespread occurence and wide host range of the H5N1 virus poses a serious threat to the human population, potentially leading to the evolution of a human influenza pandemic. Our knowledge of the behaviour of avian influenza viruses in domestic fowl and wild birds is limited. Virus infection dynamics of H7N1 low and high pathogenicity avian influenza viruses and highly pathogenic H5N1 viruses in chickens, turkeys and ducks will be compared. Extensive in-depth sequence analysis of the virus haemagglutinin gene will be undertaken to examine within-host selection of virus variants in each species-avian host range determinants. We also will determine whether in-bred chickens lines show genetic differences in susceptibility to infection and in virus shedding, and whether there are genetic differences in the immune response of the in-bred lines to infection and vaccination-these studies can provide a starting point to uncover the genetic basis of host resistance to influenza virus infection. The immune response to infection will be studied at tissue level, and protective cellular, humoral and cytokine resonses will be defined.
 
Description Outbreaks of avian influenza in poultry can be devastating, yet many of the basic epidemiological parameters have not been accurately characterised. Low pathogenicity avian influenza (LPAI) viruses of the H7 subtype generally cause mild disease in poultry. However the evolution of a LPAI virus into highly pathogenic avian influenza (HPAI) virus results in the generation of a virus that can cause severe disease and death. The classification of these two pathotypes is based, in part, on disease signs and death in chickens, but the effect of LPAI viruses in turkeys is less well understood. Low pathogenicity avian influenza (LPAI) viruses of the H7 subtype generally cause mild disease in poultry. However the evolution of a LPAI virus into highly pathogenic avian influenza (HPAI) virus results in the generation of a virus that can cause severe disease and death.
In 1999-2000 in Northern Italy, outbreaks of H7N1 low pathogenicity avian influenza virus (LPAI) were followed by the emergence of H7N1 highly pathogenic avian influenza virus (HPAI). This study investigated the transmission dynamics in turkeys of representative HPAI and LPAI H7N1 virus strains from this outbreak in an experimental setting, allowing direct comparison of the two strains. The fitted transmission rates for the two strains are similar: 2.04 (1.5-2.7) per day for HPAI, 2.01 (1.6-2.5) per day for LPAI. However, the mean infectious period is far shorter for HPAI (1.47 (1.3-1.7) days) than for LPAI (7.65 (7.0-8.3) days), due to the rapid death of infected turkeys. The comparison of transmission rates and are critically important in relation to understanding how HPAI might emerge from LPAI.
Further in these studies we discovered that the HPAI form of the virus may be present at very low levels in a bird infected with LPAI but not be expressed providing clues as to the pathways for the emergence and selection of such strains suggesting it is not an entirely random event. This information is important for disease control since it indicates early control of LPAI H5/H7 serotypes in turkeys is vital to avert greater impact from selection of an HPIA variant on the population.
Exploitation Route These are very retrospective updates and work to develop further studies understanding dynamics progressed in recent years.. Research in this area has led to successful programme of work funded by the EU under H2020 programme Deltaflu.
Sectors Agriculture, Food and Drink

 
Description Emphasised importance on global scale to competent vet authorities of the importance of controlling LPAI early in poultry and risk. Potential for underlying HPAI virus when poultry infected with LPAI has focused use of modern technologies/diagnostics to look for these subpopulations.
First Year Of Impact 2013
Sector Agriculture, Food and Drink
Impact Types Policy & public services

 
Description Advice for regulation in animal diseases
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact Member of ad-hoc groups for OIE (World Organisation for Animal Health) and FAO (Agricultural division of UN) providing advice on regulatory frameworks underpinning trade in animals and their products or disease control
 
Description International influence and advice
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact Continuous provision of advice to international governments and agencies (ie OIE,FAO,WHO) concerned with disease control. This will include a range of science topics including surveillance type and design, disease infection characteristics for spread, international threat awareness and mitigations, use of tools to effective contain disease, environmental threats from pathogen, informing human health colleagues on zoonotic risk, utility of diagnostics, control tools applicable. All data feds into effective policy making to limit cost to society, reduce burden on government and rural economy, informing the public on threat (including through EFSA and ECDC in Europe); improvements to disease control policy to respond to changes in the epidemiology of the disease.
 
Description Member of EU disease emergency task force
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact CVET missions to South Africa (2011), Hungary (2016), Bulgaria and Italy (2017). This missions review the disease situation with AI and offer advice on how to improve the disease control situation whilst providing a confidential report to the EC.
 
Description National disease control policy
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact Continuous provision of advice to government concerned with disease control. This will include a range of science topics including surveillance type and design, disease infection characteristics for spread, international threat awareness and mitigations, use of tools to effective contain disease, environmental threats from pathogen, informing human health colleagues on zoonotic risk, utility of diagnostics, control tools applicable. All data feds into effective policy making to limit cost to society, reduce burden on government and rural economy, informing the public on threat (including through FSA); improvements to disease control policy to respond to changes in the epidemiology of the disease.
 
Description Training of professionals
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact Poultry health course - modules on AI/ND delivered informed by knowledge gained through the funded research. Course physically taught and material available on line
 
Description advisory boards/committees
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
 
Title Animal models to study influenza infection kinetics 
Description Refinement and development of animal models for studying infection outcome, pathogenesis (both pathogenic and subclinical pathogens) with exotic high risk pathogens (SAPO4/ACDP3) to address basic research questions including infection outcome, pathogen tropism, transmission, mode of spread, host pathogen interaction and virus evolution. These models have had to be developed and refined to take account of legislation re animal welfare and because they need to be conducted in biosecure facilities to high standards of health and safety. 
Type Of Material Model of mechanisms or symptoms - non-mammalian in vivo 
Year Produced 2009 
Provided To Others? Yes  
Impact Refinement of human end points but maximising science output Infection kinetic data used for informing epidemiological investigations in AI disease outbreaks Host effects on pathogenesis of emerging viruses Host susceptibility investigated in a novel manner to determine natural outcomes 
 
Description AI INFECTION DYNAMICS 
Organisation The Pirbright Institute
Department Avian viral Diseases
Country United Kingdom 
Sector Private 
PI Contribution Access to international data on disease not in the public domain Provision of specialist biologicals including virus strains Contributing deep expertise on the pathogen and host infection outcomes together with context for research in a global setting Conducting animal studies to ACDP3/SAPO4: study design and execution with downstream data collection and analyses Preparation of manuscripts and other outputs for communication of the science
Collaborator Contribution Access to surveillance in Central Asia Provision of high volume gene sequencing Data analyses and preparing data for publication Study design in consultation
Impact Yes Virology, Epidemiology and Animal Science 132. Iqbal, M., Essen, S.C., Xiao, H., Brookes, S.M., Brown, I.H., and McCauley J.W. (2012) : Effect of different glycosylation patterns of the haemagglutinin glycoprotein of H7N1 avian influenza viruses on virus replication and transmission in chickens and turkeys. Influenza2012, One Influenza, One World, 11 - 13 September 2012, St. Hilda's College, Oxford, UK. Page 20.
Start Year 2013
 
Description Immunity and host 
Organisation University of Edinburgh
Department The Roslin Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution International: Prof Lonneke Vervelde (now at Edinburgh University) and Dr Christine A. Jansen, University of Utrecht. BB/E010849/1 was linked with FT7007 and financially supported by the Netherlands Organization for Scientific Research (NWO) Veni grant 016.096.049, the EU sixth framework program Flupath (grant 04220) and Impulse Veterinary Avian Influenza Research programme in The Netherlands, Dutch Ministry of Agriculture, Nature and Food Quality. National: Drs Suresh Kuchipudi, Stephen Dunham and Prof Kin-Chow Chang, Nottingham University. The data generated with this project has also informed the design of future studies including the use of transgenic chickens resistant potentially to infection with avian influenza viruses in collaboration with the Cambridge Infectious Diseases Consortium (CIDC), University of Cambridge.
Collaborator Contribution Avian Innate Immunity: Prof Lonneke Vervelde (now at Edinburgh University) and Dr Christine A. Jansen, University of Utrecht. BB/E010849/1 was linked with FT7007 and financially supported by the Netherlands Organization for Scientific Research (NWO) Veni grant 016.096.049, the EU sixth framework program Flupath (grant 04220) and Impulse Veterinary Avian Influenza Research programme in The Netherlands, Dutch Ministry of Agriculture, Nature and Food Quality. National: Drs Suresh Kuchipudi, Stephen Dunham and Prof Kin-Chow Chang, Nottingham University. The data generated with this project has also informed the design of future studies including the use of transgenic chickens resistant potentially to infection with avian influenza viruses in collaboration with the Cambridge Infectious Diseases Consortium (CIDC), University of Cambridge.
Impact Informal science exchange; unsuccessful grant applications
Start Year 2010
 
Description Immunity and host 
Organisation University of Nottingham
Country United Kingdom 
Sector Academic/University 
PI Contribution International: Prof Lonneke Vervelde (now at Edinburgh University) and Dr Christine A. Jansen, University of Utrecht. BB/E010849/1 was linked with FT7007 and financially supported by the Netherlands Organization for Scientific Research (NWO) Veni grant 016.096.049, the EU sixth framework program Flupath (grant 04220) and Impulse Veterinary Avian Influenza Research programme in The Netherlands, Dutch Ministry of Agriculture, Nature and Food Quality. National: Drs Suresh Kuchipudi, Stephen Dunham and Prof Kin-Chow Chang, Nottingham University. The data generated with this project has also informed the design of future studies including the use of transgenic chickens resistant potentially to infection with avian influenza viruses in collaboration with the Cambridge Infectious Diseases Consortium (CIDC), University of Cambridge.
Collaborator Contribution Avian Innate Immunity: Prof Lonneke Vervelde (now at Edinburgh University) and Dr Christine A. Jansen, University of Utrecht. BB/E010849/1 was linked with FT7007 and financially supported by the Netherlands Organization for Scientific Research (NWO) Veni grant 016.096.049, the EU sixth framework program Flupath (grant 04220) and Impulse Veterinary Avian Influenza Research programme in The Netherlands, Dutch Ministry of Agriculture, Nature and Food Quality. National: Drs Suresh Kuchipudi, Stephen Dunham and Prof Kin-Chow Chang, Nottingham University. The data generated with this project has also informed the design of future studies including the use of transgenic chickens resistant potentially to infection with avian influenza viruses in collaboration with the Cambridge Infectious Diseases Consortium (CIDC), University of Cambridge.
Impact Informal science exchange; unsuccessful grant applications
Start Year 2010
 
Description Immunity and host 
Organisation Utrecht University
Country Netherlands 
Sector Academic/University 
PI Contribution International: Prof Lonneke Vervelde (now at Edinburgh University) and Dr Christine A. Jansen, University of Utrecht. BB/E010849/1 was linked with FT7007 and financially supported by the Netherlands Organization for Scientific Research (NWO) Veni grant 016.096.049, the EU sixth framework program Flupath (grant 04220) and Impulse Veterinary Avian Influenza Research programme in The Netherlands, Dutch Ministry of Agriculture, Nature and Food Quality. National: Drs Suresh Kuchipudi, Stephen Dunham and Prof Kin-Chow Chang, Nottingham University. The data generated with this project has also informed the design of future studies including the use of transgenic chickens resistant potentially to infection with avian influenza viruses in collaboration with the Cambridge Infectious Diseases Consortium (CIDC), University of Cambridge.
Collaborator Contribution Avian Innate Immunity: Prof Lonneke Vervelde (now at Edinburgh University) and Dr Christine A. Jansen, University of Utrecht. BB/E010849/1 was linked with FT7007 and financially supported by the Netherlands Organization for Scientific Research (NWO) Veni grant 016.096.049, the EU sixth framework program Flupath (grant 04220) and Impulse Veterinary Avian Influenza Research programme in The Netherlands, Dutch Ministry of Agriculture, Nature and Food Quality. National: Drs Suresh Kuchipudi, Stephen Dunham and Prof Kin-Chow Chang, Nottingham University. The data generated with this project has also informed the design of future studies including the use of transgenic chickens resistant potentially to infection with avian influenza viruses in collaboration with the Cambridge Infectious Diseases Consortium (CIDC), University of Cambridge.
Impact Informal science exchange; unsuccessful grant applications
Start Year 2010
 
Description Global poultry industry 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Ad-hoc advice and numerous visits to third countries. Some advice provided to policy makers formulating control policy against AI. Data/knowledge gained form research contributed to personal CPD and expertise therein.
Year(s) Of Engagement Activity 2011,2012,2013,2014,2015,2016,2017,2018
 
Description International outreach 
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 OFFLU (OIE/FAO) international network of institutes providing global expertise on AI (http://www.offlu.net )
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012,2013,2014,2015,2016,2017,2018
 
Description International symposia on AI 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Ian Brown co-chaired this major international event presenting the latest science on AI
Year(s) Of Engagement Activity 2012,2015,2018
URL http://www.flu-lab-net.eu
 
Description Media work 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Media output through BBC countryfile raising/news raising awareness of AI threat
Year(s) Of Engagement Activity 2008
 
Description Poultry industry 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Provision of science evidence from AI research to stakeholder groups in the UK poultry industry. Data used by industry to make business decisions related to AI threat
Year(s) Of Engagement Activity 2010,2011,2012,2013,2014,2015,2016,2017,2018
 
Description Uk research fora 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact wide range of fora where UK researchers formally come together via events/meetings to exchange scientific research knowledge
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012,2013,2014,2015,2016,2017,2018
 
Description teaching 
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 Industry/Business
Results and Impact Poultry health course - modules on AI/ND delivered informed by knowledge gained through the funded research. Course physically taught and material available on line
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012,2013,2014,2015,2016,2017,2018
URL http://www.poultryhealthcourse.com