Award details

Discovering cellular responses targeted by herpesvirus tegument enzymes that are delivered by the entering virion

Reference	BB/M021424/1
Principal Investigator / Supervisor	Dr Colin Crump
Co-Investigators / Co-Supervisors
Institution	University of Cambridge
Department	Pathology
Funding type	Research
Value (£)	417,520
Status	Completed
Type	Research Grant
Start date	01/08/2015
End date	30/09/2018
Duration	38 months

Abstract

Herpesviruses cause a wide range of diseases in animals and humans, many of which have significant economic impact on livestock industries and human health. There is an urgent need to develop new and improved therapeutics to combat veterinary and human herpesvirus infections, and it is vital to increase or understanding of virus host interactions for this aim. All viruses need to modify host cells to establish infection; an important mechanism by which many viruses alter host pathways is through the activity of viral proteins delivered with the infecting virion. However, there is virtually no understanding of the specific effects on the cell caused by virion-contained proteins that are released into the cytoplasm upon virus entry. This research will address these questions using herpes simplex virus as an ideal model for herpesvirus replication. The principal focus will be on the tegument proteins vhs, pUL13, pUS3 and ICP0, well-characterised virulence factors with enzymatic activity that are conserved throughout the alphaherpesvirus family. We will generate a series of recombinant viruses that contain wild type amounts of these tegument enzymes within their virions but importantly do not express these proteins from the viral genome. This will allow us to precisely determine the specific effects of these delivered tegument enzymes on cellular pathways using state-of-the-art proteomics to analyse the protein content of the whole cell as well as specific cellular compartments. This research will also utilise advanced super-resolution microscopy to investigate the release, transport, and destination of herpesvirus tegument enzymes once they are delivered into the cell, at nanometre resolution. The combination of these cutting-edge and innovative techniques will allow us to make great advances in understanding cellular defence strategies and the countermeasure used by herpesviruses to efficiently establish infection.

Summary

Herpesviruses are a very large family of viruses that cause many diseases in animals and humans. In particular many viruses that belong to the alphaherpesvirus subfamily cause significant disease and economic losses in the horse, cow, pig and poultry industries. Viruses of this herpesviruses subfamily that infect humans generally cause relatively benign diseases in healthy people, such as cold sores and genital herpes (herpes simplex virus) or chickenpox and shingles (varicella-zoster virus). However, these viruses do cause severe or life-threatening conditions, especially in immuno-suppressed people, such as herpes keratitis that is a leading cause of blindness, and herpes encephalitis that is commonly fatal even after antiviral drug treatment. Once infected with these viruses, they are there for life: all herpesviruses establish a dormant (so called latent) infection for the lifetime of the host, usually within the sensory nervous system for alphaherpesviruses, which cannot be treated with available drugs or prevented by available vaccines. Periodic episodes of virus reactivation from these latently infected cells can cause recurrence of disease and allows the virus to spread to uninfected organisms. Because of the many diseases caused by these viruses in such a wide range of animals as well as humans, there is an urgent need to develop improved antiviral drugs and vaccines. To be able to effectively fight virus infections it is vital to understand as much as possible about how they infect and reproduce inside the cells of the body. Cells have many ways of protecting themselves from viruses, and conversely viruses have evolved many ways of overcoming these defences. There is still a great deal we don't understand about these 'host defences' and 'virus countermeasures' and the more we can discover about how cells defend themselves, and how viruses overcome these defences, the better able we will be to develop new ways of fighting infection. The focus of this research is to discover the changes to host cells that are brought about by specific viral enzymes that are contained within herpesvirus particles and released into the infected cell as soon as the virus enters it. These viral enzymes are vital for herpesvirus to evade host defences, although we know virtually nothing about the specific effects of these enzymes as they are released into a cell by the virus. We will use state-of-the-art protein analysis techniques that enable us to detect and quantify thousands of proteins at once to discover the specific proteins of the cell that are targeted by these delivered viral enzymes. We will also use cutting-edge microscopy (so called super-resolution microscopy) to analyse the fate of these viral enzymes as they are delivered into cells by the incoming virus; these powerful new imaging techniques now provide us with the ability to detect and monitor single molecules in cells, allowing us to observe virus-host interactions at an unprecedented level of detail. For this work we will be using the human pathogen herpes simplex virus, as the most well-defined and tractable model of this important family of viruses, so we can make rapid and efficient progress in this research The cellular pathways uncovered by this work are likely to include many cell defence systems that are crucial for cells to repel virus infection and so undoubtedly will be important defences against a broad range of viruses that infect different organisms. The new information that we will discover in these studies will provide a much greater understanding of how cells respond to infection as well as ways viruses can overcome these defences. This will ultimately lead to new and improved ways of fighting herpesviruses, as well as many other important viruses that cause significant animal and human diseases throughout the world.

Impact Summary

This research project aims to identify novel cellular pathways specifically targeted by herpesvirus tegument enzymes that are delivered to infected cells as part of the incoming virus particle. The primary beneficiaries of this work will be academic researchers investigating the mechanisms of virus replication and anti-viral host defences. However, this research will also lay the foundations for impact in the following areas: 1. Academia The extensive datasets that we will generate on host responses modulated by virion-delivered vhs, pUL13, pUS3 and ICP0, all important virulence factors, will provide much information of interest to researchers in a broad range of fields. This includes scientists studying a wide range of herpesviruses and other unrelated viruses, as well as researchers investigating host immune mechanisms. In addition, our work on super-resolution microscopy will have impacts on physical scientists and engineers developing these advanced imaging techniques. 2. Commercial Sector This research will provide us with a much deeper understanding of how viruses take control of the cellular machinery. This will undoubtedly have impacts on the future development of new antiviral therapeutics, and such knowledge will be of great interest to pharmaceutical and biotechnology companies that work in animal and human infectious diseases, and in particular veterinary and human herpesviruses. In addition, methodologies and reagents that we will develop could be useful tools for research in the UK biotechnology business sector. 3. Society Success in the development of antiviral therapies to combat herepsvirus infection would have long-term benefits for the health and wellbeing of economically important livestock as well as people, both in the developed and developing worlds. Herpesviruses cause major problems in many equine, bovine, porcine and avian species, and can have devastating impacts on these industries throughout the world. In addition herpesvirus infections are a major problem in transplantation medicine and are the leading infectious causes of neonatal abnormalities and blindness. Any potential for combating these important viral pathogens could have huge benefits for society. While such impacts are beyond the time frame of this research project, due to the lengthy nature of drug discovery and development, this research will provide excellent candidates for targeted development in future antiviral research and design. 4. Professional Development The appointed postdoctoral research associate (Dr Albecka-Moreau) will gain a plethora of new skills, including experience in state-of-the art proteomics techniques, as well as further developing her skills in the cross-disciplinary research that is involved in developing cutting-edge super-resolution microscopy technology. This will significantly enhance the impact of this young scientist, who has an excellent chance of becoming a leader in life-sciences research in the future. In addition, this research will expand the intellectual and practical training opportunities for current and future postgraduate research students, as well as several undergraduate students during their laboratory research projects at the University of Cambridge, thereby providing an improved skill base and enhancing the knowledge economy of the UK.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Immunology, Microbiology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

I accept the terms and conditions of use (opens in new window)

export PDF file

back to list new search