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Host immune responses to CSFV infection and investigation of improved intervention tools - SE2201

Description
Classical swine fever virus (CSFV) remains an important pathogen that poses a serious threat to pig production worldwide. Despite the existence of live attenuated and marker subunit vaccines neither are ideal for effective control of the disease. This proposal aims to further our understanding of the virus’s interaction with the host immune system to enable the design of better intervention strategies; either by the development of improved vaccines or novel strategies, such as immunomodulation of the host’s innate immune defenses.

Our initial objective is to dissect the interactions of CSFV with myeloid cells, in particular dendritic cells (DCs), which are specialised antigen presenting cells that bridge the innate and adaptive arms of the immune system. Strains of CSFV with varying virulence result in different outcomes to infection; virulent strains replicate rapidly after infection and result in death, whereas less virulent strains can be controlled by the host’s immune system. By applying a new, fully annotated, porcine microarray that covers the entire porcine genome, we aim to scan the complete set of transcriptional changes that occur both with virulent and non-virulent strains to identify host pathways that could be boosted or knocked down by an intervention to prevent or reduce disease spread.

Our second objective is to investigate on the efficacy of type I, II and III interferons (IFNs) in preventing CSFV infection of pigs. IFNs have been used successfully for treatment of viral infections such as hepatitis C virus, which is related to CSFV. Initial studies in cell cultures will identify the porcine interferons with the highest and longest anti-CSFV activity, and if applying combinations of more than one IFN can provide a synergistic effect. These in vitro studies will then enable us to select the best candidates to evaluate in animal experiments. The use of IFN treatments in livestock species has been hampered by high costs associated with production of recombinant proteins, however the use of viral vectored delivery systems would provide a more cost effective solution. We therefore aim to investigate the ability of an adenovirus vector system to deliver IFN to pigs and assess the efficacy of the selected interferons to prevent CSFV infection.

The development of improved marker vaccines would significantly enhance control of CSFV. Current marker vaccines are based on the E2 protein. However, immunity to CSFV involves T cell responses, that may involve the secretion of anti-viral cytokines and cytotoxic effector mechanisms, as well as the induction of neutralising antibody against the E2 protein. Data we suggests that priming of T cell responses can confer a rapid protection and we aim to investigate formulation of vaccine antigens into nanoparticles to efficiently prime both arms of the immune system. We propose to evaluate formulations of the CSFV viral proteins NS3 and E2, together with different pathogen associated molecular patterns (PAMPs), which are required to effectively induce T cell and antibody responses. These formulations will be evaluted in vitro using porcine DC based assays and the most promising formulations tested in small scale immunogenicity trials in pigs.
Objective
Objective 1: Analysis of the interaction of CSFV with myeloid cells
1.1 Analyse the effects of CSFV infection on blood monocytes and DC populations.

Objective 2: Investigation of IFNs as a metaphylactic intervention against CSFV
2.1. Analyse the in vitro inhibition of CSFV by IFNs to allow rational selection of interferon types for further testing in vivo.
2.2. Investigate appropriate systems for delivery of the selected porcine IFNs and characterise the host immune reactions induced.
2.3. Assess the efficacy of selected treatments in the prevention of CSFV infection.

Objective 3: Optimisation of a particulate vaccine formulation for induction of antibody and cell-mediated immune responses to CSFV antigens
3.1 Evaluate nanoparticulate formulation for induction of antibody and cell-mediated immune responses to CSFV vaccine candidate antigens.
Project Documents
• EVID4 - Final project report : SE2201 final report 15.02.2018   (1110k)
Time-Scale and Cost
From: 2012

To: 2017

Cost: £747,856
Contractor / Funded Organisations
A H V L A (Animal Health and Veterinary Laboratories Agency - AHVLA)
Keywords
Classical Swine Fever              
Immunity