Gamma-herpesvirus dissemination in vivo

Lead Research Organisation: University of Cambridge
Department Name: Finance

Abstract

The gamma-herpesviruses are a major cause of disease. This reflects the capacity of viral gene expression to evade the host defence mechanisms encoded by the human genome. While there has been enormous investment in the analysis of both host and pathogen DNA sequences, we have very little idea how the relevant proteins interact in vivo. With the gamma-herpesviruses, this reflects a relative lack of suitable experimental models with which to analyze host / pathogen interactions. We are using the MHV-68 model to address, in an important class of complex parasites, this deficit in our understanding of immune gene function .
Our research findings are communicated principally in specialist journals. We regularly present unpublished data at scientific meetings. Information is communicated directly to the public at university open days, departmental seminars and via the departmental and divisional web sites.

Technical Summary

The gamma-herpesviruses represent a significant and difficult clinical problem. They are complex pathogens, with 80-100 genes, that persist and remain infectious despite established immunity. Our knowledge of how individual genes contribute to the pathogenesis of human gamma-herpesviruses is extremely limited, since modified viruses can be studied only in vitro. We are therefore using a natural murid gamma-herpesvirus, MHV-68, to identify genes crucial to in vivo host colonization. All gamma-herpesviruses are latent in lymphocytes and the entry of virus into lymphoid tissue is a key event. There is no viraemia. Instead, an initial epithelial infection probably reaches lymphoid tissue via direct contact between infected and uninfected cells. We have preliminary evidence that gp48, a product of the MHV-68 ORF27 gene, which has homologues in all gamma-herpesviruses, is a critical determinant of cell to cell spread in vitro; and that a multiple membrane spanning protein encoded by ORF58 is required for gp48 expression at the cell surface. The aims of this project are to determine how gp48 and the ORF58 gene product act at a molecular level and to characterize the effect of gp48 and ORF58 deficits in vivo.
 
Description MRC program grant
Amount £1,056,697 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 06/2008 
End 06/2013
 
Title antibodies + viruses 
Description generated monoclonal antibodies against viruses, and recombinant viruses 
Type Of Material Antibody 
Year Produced 2006 
Provided To Others? Yes  
Impact unknown as yet 
 
Title luciferase imaging 
Description system for imaging virus infection in live mice 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2008 
Provided To Others? Yes  
Impact reduced mouse use 
 
Description WEHI collaboration 
Organisation The Walter and Eliza Hall Institute of Medical Research (WEHI)
Department Immunology Division
Country Australia 
Sector Academic/University 
PI Contribution collaborative experiments with Gabrielle Belz
Collaborator Contribution joint research project
Impact 17109468 18025195 travelling fellowship from Royal Society to visit WEHI lab joint Wellcome Trust project grant
 
Description bbsrc case 
Organisation Immunobiology Ltd, Babraham, UK
Country United Kingdom 
Sector Private 
PI Contribution BBSRC CASE studentship with Immunobiology
Collaborator Contribution discussion of project provision of biotechnology experience to student
Impact 19625459
Start Year 2007
 
Description lisbon collaboration 
Organisation University of Lisbon
Country Portugal 
Sector Academic/University 
PI Contribution joint research projects
Collaborator Contribution joint research projects
Impact 19605591 19088269 18846211
 
Description department open days 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact virology presentation at department open day

information exchange
Year(s) Of Engagement Activity 2006,2007,2008