Structural studies on human viruses

Lead Research Organisation: University of Glasgow

Abstract

We wish to understand the structure of virus particles and how they interact with the host cell. This can provide insights into many aspects of virus biology and may suggest strategies for treatment. The Main virus being studied is herpes simplex virus, which is a widespread human pathogen causing a variety of diseases. Virus replication and virus particle formation are complex, multistage processes involving the products of many virus genes. We are determining the three-dimensional structure of the virus at different stages during its replication cycle to determine how the structure dictates the assembly and disassembly mechanisms. This is combined with molecular genetic analyses to produce a comprehensive description of the processes leading to the formation and spread of infectious virus particles.

Technical Summary

Knowledge of the structure of viruses and how they interact with the host cell is essential for understanding the processes involved in infection. Virion morphogenesis is a central feature of the life cycle of any virus, and a clear understanding of this process can provide insights into many aspects of virus biology and may suggest possible strategies for therapeutic intervention. We use both structural and molecular genetic approaches to visualise virus particles at various stages during their replication. Herpesviruses are double-stranded DNA viruses that have icosahedral particles, which are surrounded by asymmetrical protein and lipid layers. The structure of the herpesvirus virion is under study in collaboration with Wah Chiu at Baylor College of Medicine in Houston. Both icosahedral and tomographic reconstruction approaches are being used to visualise the symmetrical and asymmetrical features of the particles and uncover the relationships between them. These structural analyses are now being extended to examine virus particles interacting with host cells at various stages during entry, transport and assembly. To facilitate these analyses, we employ correlative microscopy techniques, in which the use of tagged proteins allows the same labelled features to be observed both by light and electron microscopy. This helps us to identify and visualise infrequent, but interesting assemblages or behaviours in the challenging environment of the infected cell. In parallel studies, the functions of virus structural proteins and their interactions with cellular proteins during the processes of infection and virus maturation, are being examined by molecular biological, mutational and microscopical studies. These complementary analyses are helping to produce fundamental insights into the processes controlling the assembly and dis-assembly, of these important pathogens.

Publications

10 25 50
 
Description Cryo-Electron Microscopy Equipment Grants
Amount £4,400,000 (GBP)
Funding ID MC_PC_17135 
Organisation LifeArc 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2017 
End 07/2022
 
Description Herpes simplex virus entry 
Organisation University of Cologne
Department Center for Biochemistry
Country Germany 
Sector Academic/University 
PI Contribution Collection of data, preparation of manuscripts, planning and direction of research.
Collaborator Contribution Collection of data, preparation of manuscripts, planning and direction of research.
Impact Publication of a manuscript in 2011
Start Year 2008
 
Description Herpes simplex virus transport mechanisms 
Organisation National Center for Scientific Research (Centre National de la Recherche Scientifique CNRS)
Department Laboratory of Molecular and Structural Virology CNRS
Country France 
Sector Public 
PI Contribution Development and preparation of reagents, collection of data, preparation of manuscripts, planning and direction of research.
Collaborator Contribution Development and preparation of reagents, collection of data, preparation of manuscripts, planning and direction of research.
Impact Publication of four manuscripts in 2010, 2011 and 2012
Start Year 2009
 
Description Non-adaptive immune resposes to HSV 
Organisation Aarhus University
Department Department of Biomedicine
Country Denmark 
Sector Academic/University 
PI Contribution Collection of data, preparation of manuscripts, planning and direction of research.
Collaborator Contribution Collection of data, preparation of manuscripts, planning and direction of research.
Impact Publication of a manuscripts in 2011 and 2012
Start Year 2010
 
Description Structural studies on herpes simplex virus 
Organisation Baylor College of Medicine
Department National Institute for Macromolecular Imaging
Country United States 
Sector Academic/University 
PI Contribution Development and preparation of reagents, collection of data, preparation of manuscripts, planning and direction of research.
Collaborator Contribution Development and preparation of reagents, collection of data, preparation of manuscripts, planning and direction of research. Travel and accommodation costs for collaborative visits (3 working visits to Houston in 2010, 1 in 2011, 2 in 2012).
Impact Publication of 18 papers and 3 reviews/chapters, 5 since 2006. Disciplines involved cover molecular virology and structural biology.
 
Description herpes simplex virus neuronal transport 
Organisation University of Sydney
Department Westmead Milleninium institute
Country Australia 
Sector Academic/University 
PI Contribution Development and preparation of reagents, preparation of manuscripts.
Collaborator Contribution Development and preparation of reagents, collection of data, preparation of manuscripts, planning and direction of research.
Impact Publication of three papers, two since 2006