Identification of cellular genes that affect host range restriction of influenza virus

Lead Research Organisation: Imperial College London
Department Name: Dept of Virology

Abstract

Influenza viruses pose a pandemic threat to human health because avian influenza viruses can sometimes acquire the ability to replicate in and transmit between people. Since humans have no pre-existing immunity to these strains, the whole world is susceptible and the virus spreads rapidly causing excess morbidity and mortality. The way in which this might happen is for a strain of bird flu to acquire a mutation in its genetic makeup that helps it replicate faster in human cells. We know about some of the mutations by which this switch is achieved, but we do not understand the mechanism behind them. In this project we will identify genes from the chicken and from the human host which might be important in determining whether a particular virus can replicate in either host. Then we will design experiments to discover why they are important for influenza virus replication. This basic scientific information will allow us to understand how to predict which strains of virus are the ones most likely to cause pandemics, and will also assist design of novel antiviral compounds that target essential steps of the virus cycle.

Technical Summary

The H5N1 avian strain of influenza A virus is posing a pandemic threat. It is paramount to understand and predict the mechanism by which the virus might acquire increased replicative ability and thus transmit between humans. Avian influenza viruses are usually restricted in their replication in humans but it is well documented that mutations in the PB2 component of the heterotrimeric polymerase complex can adapt the virus for replication in humans. However the mechanism by which that occurs is not clear. We hypothesize that the polymerases of avian influenza viruses do not interact efficiently with a cellular component in human cells and that this interaction would be required during replication. We seek to identify such genes and discover their role in enhancing influenza virus replication. The approach we will take has proved successful in a preliminary study. We supply fragments of chicken chromosome as a cDNA library to mammalian cells which otherwise are not permissive to avian influenza, and screen for those cells in which replication is enhanced. Isolation of individual chicken cDNAs will allow their identification and experiments designed to uncover why such genes enhance avian virus replication will be performed. Understanding these mechanisms are of basic scientific interest, but will also inform surveillance and may direct strategies for novel antiviral therapies.
 
Description EU FP7 ANTIFLU
Amount £372,704 (GBP)
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 06/2011 
End 05/2015
 
Title chicken cDNA library 
Description A high quality cDNA library made from chicken mRNAs 
Type Of Material Technology assay or reagent 
Year Produced 2008 
Provided To Others? Yes  
Impact THis library has been used by Professosr Juergen Haas to screen for interacting proteins of chickens with avain influenza virus proteins. As a results of our collaboration in this area. supported a new research proposal by Dr Haas to BBSRC 
 
Description ANTIFLU 
Organisation Max Planck Society
Country Germany 
Sector Charity/Non Profit 
PI Contribution Providing specialist influenza experience and research
Collaborator Contribution Access ot a large data set pf host genes that may be invovled in influenza replication. Access to new technologies
Impact None yet
Start Year 2011
 
Description FLUPIG 
Organisation Animal Health And Veterinary Laboratories Agency (AHVLA)
Country United Kingdom 
Sector Public 
PI Contribution Investigating teh role of polymerase in restriction of avian influenza in pigs
Collaborator Contribution Investigating the role of pigs in pandemci influenza
Impact Investigation of influenza polymerase activity in pig cells. Moncorgé O, Long JS, Cauldwell AV, Zhou H, Lycett SJ, Barclay WS. J Virol. 2012 Oct 17. [Epub ahead of print]
Start Year 2010
 
Description Parliamentray Scientific Committee 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Invited talk to PSC April 2011 on influenza pandemics and dinner afterwards with committe members

Article written for PSC magazine
Year(s) Of Engagement Activity 2011