Host range determinants of influenza viruses

Lead Research Organisation: MRC National Inst for Medical Research

Abstract

Three pandemics of influenza appeared in the twentieth century. In the 1918 pandemic an estimated 40 million people died from influenza infection. The associated mortality of the 1918 virus was remarkably high- the pandemics of 1957 and 1968 were associated with a much lower death rate. Pandemic influenza viruses emerge from influenza viruses found in avian species. The appearance over the last decade of H5N1 bird flu in Asia with its associated high human mortality rate highlights the risks of a new pandemic virus developing. The current H5N1 bird flu can infect humans but the infected individuals seem largely unable to transmit the infection to others. Should the virus acquire the ability to spread between individuals more efficiently, the possibility that a pandemic might occur is a major concern. We do not know all the factors that govern how an avian influenza virus gains the ability to infect and spread between humans. Avian influenza viruses vary in their ability to replicate in human cells in culture. We wish to understand why some avian influenza viruses are able to replicate efficiently in human cells but others are not, and we wish to discover the host factors that can limit the infection. We hope that with this knowledge we will be in a better position to anticipate the risks of avian influenza viruses jumping species to generate a pandemic virus.

Technical Summary

Influenza viruses infect a variety of species; humans, horses and pigs are the main mammalian hosts of the virus in which infection is sustained. However avian species, particularly water fowl and gulls, harbour a very wide variety of influenza viruses and it is from the avian pool of influenza viruses that new pandemic strains of human influenza viruses arise. The currently ongoing infection of humans with H5N1 avian influenza viruses highlights the risk of infection from viruses normally present in the bird population to evolve into new pandemic human strains of virus. The factors that limit the infection of influenza viruses to their natural hosts are not clearly understood. It is known that the interaction between a virus particle and its receptor on the cell is a vital feature that limits host range of viruses but other factors following entry of virus into the cell also determine the outcome of infection. In this work we are studying aspects of host range restriction of avian influenza viruses that limit their ability to infect and propagate in mammalian cells. Using panels of cell lines that are defective in innate anti-viral responses to infection we are examining how these cells influence the ability of human and avian viruses to replicate productively. Additionally we wish to uncover which virus factors influence the differences. We are initially focussing on cells that are defective in the induction of interferon-beta and other genes similarly controlled by interferon regulatory factor 3 (IRF-3), and on cells that are defective for interferon signalling through defects in the Jak/Stat pathway of signal transduction. We hope to define some of the factors of the host-pathogen interaction that are critical for virus host range. The results from this work we hope will put us in a better position to assess the risk of an emerging avian influenza infection acquiring the ability to infect new host species.

Publications

10 25 50

 
Description Commons select committe on scientific advice and evidence in emergencies
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
Impact The committee was reviewing the UK management of the H1N1 influenza pandemic of 2009-2010. I contributed to the MRC section of the RCUK submission and I contributed as Director of the WHO Collaborating Centre for Reference and Research on Influenza a detailed reply on the international role UK played in the pandemic.
 
Description WHO Influenza Training and Vaccine Selection, antiviral resistance monitoring.
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
Impact Vaccine strain selection meetings results in updating the influenza vaccine on a twice-yearly basis. Training workshops lead to the development of the WHO Global Influenza Surveillance Network.
 
Description WHO Influenza Vaccine Selection Committee
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
Impact The WHO advisors reach a recommendation twice yearly on the optimal composition of influenza vaccines, once for the Northrn Hemisphere and once for the Southern Hemisphere influenza season.
 
Description BBSRC-Research Grant Award-2008
Amount £446,135 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start  
End 07/2013
 
Description IFPMA-International Federation of Pharmaceutical Manufaturers&Associations/IFPMA
Amount £290,189 (GBP)
Organisation International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) 
Sector Charity/Non Profit
Country Switzerland
Start 06/2010 
 
Description Wellcome-Research Grant-2008
Amount £218,147 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2008 
End 01/2010
 
Title Haemagglutinin 
Description Sample of Haemagglutinin protein 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Material supplied to commercial body under a Materials Use Licence 
 
Description Animal Influenza characteristion 
Organisation Medical Research Council (MRC)
Department MRC Human Immunology Unit
Country United Kingdom 
Sector Public 
PI Contribution We have received funding on two BBSRC project grants from 2006. These were focussing on the transmission dynamics, pathogenicity, immune responses and modelling of influenza viruses in avian hosts. We collaborate on BBSRC funded projects on swine influenza infections in pigs and pig workers.
Collaborator Contribution We have a long term collaboration with the Institute fro Animal Health on influenza virus biology and on pestivirus biology We work closely with collaborators on influenza viruses and pestivirusesWe have a long term collaboration with the Veterinary Laboratories Agency on animal influenza viruses. We have joint BBSRC project grant funding.We have a long standing collaboration on animal influenza modellingWe collaborate on influenza virus transmission in experiential animals and field studies.Two collaborations have been set up. One with Dr. Ling Pei Ho to study how H5N1 avian influenza viruses replicate in wild-type and mice transgenic for aspects of innate immunity. The second collaboration is with Dr. Kirsten Luhn to provide advice and viruses for her studies on the replication of influenza viruses in cells of the immune system.
Impact Publications from collaborative work.
 
Description Animal Influenza characteristion 
Organisation St George's University of London
Department Department of Basic Medical Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We have received funding on two BBSRC project grants from 2006. These were focussing on the transmission dynamics, pathogenicity, immune responses and modelling of influenza viruses in avian hosts. We collaborate on BBSRC funded projects on swine influenza infections in pigs and pig workers.
Collaborator Contribution We have a long term collaboration with the Institute fro Animal Health on influenza virus biology and on pestivirus biology We work closely with collaborators on influenza viruses and pestivirusesWe have a long term collaboration with the Veterinary Laboratories Agency on animal influenza viruses. We have joint BBSRC project grant funding.We have a long standing collaboration on animal influenza modellingWe collaborate on influenza virus transmission in experiential animals and field studies.Two collaborations have been set up. One with Dr. Ling Pei Ho to study how H5N1 avian influenza viruses replicate in wild-type and mice transgenic for aspects of innate immunity. The second collaboration is with Dr. Kirsten Luhn to provide advice and viruses for her studies on the replication of influenza viruses in cells of the immune system.
Impact Publications from collaborative work.
 
Description Animal Influenza characteristion 
Organisation The Pirbright Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution We have received funding on two BBSRC project grants from 2006. These were focussing on the transmission dynamics, pathogenicity, immune responses and modelling of influenza viruses in avian hosts. We collaborate on BBSRC funded projects on swine influenza infections in pigs and pig workers.
Collaborator Contribution We have a long term collaboration with the Institute fro Animal Health on influenza virus biology and on pestivirus biology We work closely with collaborators on influenza viruses and pestivirusesWe have a long term collaboration with the Veterinary Laboratories Agency on animal influenza viruses. We have joint BBSRC project grant funding.We have a long standing collaboration on animal influenza modellingWe collaborate on influenza virus transmission in experiential animals and field studies.Two collaborations have been set up. One with Dr. Ling Pei Ho to study how H5N1 avian influenza viruses replicate in wild-type and mice transgenic for aspects of innate immunity. The second collaboration is with Dr. Kirsten Luhn to provide advice and viruses for her studies on the replication of influenza viruses in cells of the immune system.
Impact Publications from collaborative work.
 
Description Animal Influenza characteristion 
Organisation University of Cambridge
Department Department of Applied Mathematics and Theoretical Physics (DAMTP)
Country United Kingdom 
Sector Academic/University 
PI Contribution We have received funding on two BBSRC project grants from 2006. These were focussing on the transmission dynamics, pathogenicity, immune responses and modelling of influenza viruses in avian hosts. We collaborate on BBSRC funded projects on swine influenza infections in pigs and pig workers.
Collaborator Contribution We have a long term collaboration with the Institute fro Animal Health on influenza virus biology and on pestivirus biology We work closely with collaborators on influenza viruses and pestivirusesWe have a long term collaboration with the Veterinary Laboratories Agency on animal influenza viruses. We have joint BBSRC project grant funding.We have a long standing collaboration on animal influenza modellingWe collaborate on influenza virus transmission in experiential animals and field studies.Two collaborations have been set up. One with Dr. Ling Pei Ho to study how H5N1 avian influenza viruses replicate in wild-type and mice transgenic for aspects of innate immunity. The second collaboration is with Dr. Kirsten Luhn to provide advice and viruses for her studies on the replication of influenza viruses in cells of the immune system.
Impact Publications from collaborative work.
 
Description Animal Influenza characteristion 
Organisation University of Cambridge
Department Department of Veterinary Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We have received funding on two BBSRC project grants from 2006. These were focussing on the transmission dynamics, pathogenicity, immune responses and modelling of influenza viruses in avian hosts. We collaborate on BBSRC funded projects on swine influenza infections in pigs and pig workers.
Collaborator Contribution We have a long term collaboration with the Institute fro Animal Health on influenza virus biology and on pestivirus biology We work closely with collaborators on influenza viruses and pestivirusesWe have a long term collaboration with the Veterinary Laboratories Agency on animal influenza viruses. We have joint BBSRC project grant funding.We have a long standing collaboration on animal influenza modellingWe collaborate on influenza virus transmission in experiential animals and field studies.Two collaborations have been set up. One with Dr. Ling Pei Ho to study how H5N1 avian influenza viruses replicate in wild-type and mice transgenic for aspects of innate immunity. The second collaboration is with Dr. Kirsten Luhn to provide advice and viruses for her studies on the replication of influenza viruses in cells of the immune system.
Impact Publications from collaborative work.
 
Description Animal Influenza characteristion 
Organisation Veterinary Laboratories Agency
Country United Kingdom 
Sector Public 
PI Contribution We have received funding on two BBSRC project grants from 2006. These were focussing on the transmission dynamics, pathogenicity, immune responses and modelling of influenza viruses in avian hosts. We collaborate on BBSRC funded projects on swine influenza infections in pigs and pig workers.
Collaborator Contribution We have a long term collaboration with the Institute fro Animal Health on influenza virus biology and on pestivirus biology We work closely with collaborators on influenza viruses and pestivirusesWe have a long term collaboration with the Veterinary Laboratories Agency on animal influenza viruses. We have joint BBSRC project grant funding.We have a long standing collaboration on animal influenza modellingWe collaborate on influenza virus transmission in experiential animals and field studies.Two collaborations have been set up. One with Dr. Ling Pei Ho to study how H5N1 avian influenza viruses replicate in wild-type and mice transgenic for aspects of innate immunity. The second collaboration is with Dr. Kirsten Luhn to provide advice and viruses for her studies on the replication of influenza viruses in cells of the immune system.
Impact Publications from collaborative work.
 
Description Within host variation in influenza viruses in infected poultry 
Organisation The Pirbright Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution With the Institute for Animal Health and the Animal health Veterinary Laboratories Agency we have a BBSRC funded project to examine how avian influenza viruses might vary over the course of infection in different avian hosts.
Collaborator Contribution This is an ongoing project fuinded by BBSRCThis is a BBSRC funded collaborative project with IAH, NIMR and VLA.
Impact A publication : McCauley et al. PhilTrans. Roy. Soc, 2009 and an addtional submission is under consideration for publication.
 
Description Within host variation in influenza viruses in infected poultry 
Organisation Veterinary Laboratories Agency
Country United Kingdom 
Sector Public 
PI Contribution With the Institute for Animal Health and the Animal health Veterinary Laboratories Agency we have a BBSRC funded project to examine how avian influenza viruses might vary over the course of infection in different avian hosts.
Collaborator Contribution This is an ongoing project fuinded by BBSRCThis is a BBSRC funded collaborative project with IAH, NIMR and VLA.
Impact A publication : McCauley et al. PhilTrans. Roy. Soc, 2009 and an addtional submission is under consideration for publication.
 
Description Presentaion to European Medicines Ageny 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact The conclusions of the WHO Influenza Vaccine Selection meetings are presented to the European Medicicnes Agency for them to make a europesan-wide directive for the most appropraite influenza strain to be included in the following year's influenza vacine.

The impact is that the the recommednations that we (1 from NIMR and 8 others from other WHO Collboating Centres or Essential Reference labortories) reach as WHO advisors on the composition of influenza vaccines is put into practice.
Year(s) Of Engagement Activity 2010,2011
 
Description Public Lecture, Kuala Lumpur, Malaysia 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact A public lecture was hosted as a public out-reach programme by a Bioinformatics company. The audience was the general public but was made up of Health Care Professionals. The topic was pandemic H1N1 influenza.

Awareness of the audience on the current state of knowledge on the H1N1 pandemic.
Year(s) Of Engagement Activity 2009
 
Description Radio and Television interviews 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Interviews on Radio 4 (approx 6 times), Radio 5, Radio Wales, the World Service, Sky TV, ITV News, BBC News, German TV, Ukraine TV, and many more

Public awareness of the H1N1 pandemic.
Year(s) Of Engagement Activity 2009
 
Description Television and Radio Interviews 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Interview on GMTV and BBC Radio Northern Ireland about influenza vaccination and influenza vaccination policy

Increased information to the public on influenza vaccination.
Year(s) Of Engagement Activity 2007,2009
 
Description Television and Radio Interviews 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Interviewed about H5N1 avian influenza virus

Increased public awareness of the risk of H5N1 influenza viruses in the UK and elsewhere
Year(s) Of Engagement Activity 2007,2008