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Classical swine fever virus evasion of innate immune defences - SE0785

Description
Outbreaks caused by the Classical Swine Fever Virus (CSFV) are currently controlled by stamping out of infected and neighbouring herds, as available live attenuated vaccines provide no means for discriminating between vaccinated and infected animals. Subunit marker vaccines that allow this discrimination are available but only induce an effective immunity after several weeks and multiple doses, which is not sufficient for control of an emergency situation. The large scale culling of healthy animal for the purposes of controlling animal diseases is undesirable and so interventions that are able to prevent viral infection and spread in the early stages of an outbreak are required to reduce the need for large scale culling for control disease.

The mammalian innate immune system is the first line of the host`s defence against infection. It is triggered by exposure to a pathogen and results in limiting the early proliferation and spread of infectious agent, allowing time for the host`s adaptive immune response to specifically target the particular pathogen and develop long lasting protection. Interventions that stimulate the innate immune response have the potential to provide rapid and broad-spectrum protection from disease and could be particularly valuable for controlling outbreaks of disease.

However the Classical Swine Fever Virus is able to avoid the innate immune system. The virus is able to antagonise the antiviral effects of interferon and prevent apoptosis; the mechanisms by which the host usually protects itself by eliminating infected cells and preventing viral spread to neighbouring cells.

The aim of this proposal is to further our understanding of the mechanisms by which the virus is able to avoid these innate immune response. This knowledge will be invaluable for the development of intervention strategies that seek to manipulate the host’s innate immune response to prevent the virus from initiating new infections. The dissemination of this knowledge will ultimately reduce the suffering of animals and assist the farming industry by reducing losses caused by this exotic disease and thus helping to ensuring efficient markets. The research also addresses one of the aims of Defra`s science and innovation strategy to develop the most effective approaches for the prevention and control of exotic diseases.

The first objective of this proposal is to investigate the molecular signalling pathways that lead to apoptosis, and hence virus elimination, to identify which step or steps in the pathway are inhibited by the virus. During a previous project we identified that the CSFV protein Npro has an essential role in inhibiting the production of interferon in infected cells. The second objective of this project is to establish the role that this and other viral proteins have in the pathogenesis and virulence of the virus by identifying host proteins that the viral proteins interact with. Finally we will investigate the effects of different types of interferon on CSFV infection to provide information vital for efforts in the use of interferon as a method to stimmulate the host innate immunity as a defense against infection.
Objective
Objective 1: How does CSFV inhibit apoptosis?
CSFV inhibits apoptosis induced by dsRNA and we have established that this inhibition is upstream of the effector caspases 3/7, the regulatory caspases 8 and 9 and that there may be multiple points of inhibition in the apoptotic pathway, both upstream of and at the level of the mitochondria. The first objective of this proposal is to investigate steps in the apoptotic pathway, to identify which reactions are targeted by the virus.

Objective 2: Investigation of the role of viral proteins in pathogenesis and virulence?
The viral protein Npro has been identified to be important for virulence and pathogenesis of CSFV; it is involved in inhibiting the production of interferon and apoptosis by CSFV. The second objective of this proposal is aimed at identifying host proteins that this viral protein is interacting with to exert these effects. Most viruses have multiple mechanisms that antagonise the innate immune system and this objective also aims to investigate the involvement of another viral protein in pathogenesis and virulence.

Objective 3: Analysis of the effects of interferon (IFN) on CSF infection
Porcine IFN is active against CSF in cell cultures. However, an approach using expression of recombinant porcine IFN, which inhibited foot and mouth disease in swine, was less successful when applied against CSF. The third objective of this proposal is to investigate some of the reasons why this approach may have been unsuccessful, to inform future investigations into the use of IFN as a means of CSFV control.
Project Documents
• Final Report - SID5A : Classical swine fever evasion of innate immune defenses   (544k)
Time-Scale and Cost
From: 2006

To: 2009

Cost: £573,371
Contractor / Funded Organisations
Veterinary Laboratories Agency
Keywords
Animal Diseases              
Animal Health              
Classical Swine Fever              
Control              
Immunity              
Plants and Animals              
Fields of Study
Animal Health