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Project ID: QLK2-CT-2001-01374
Finanziato nell'ambito di: FP5-LIFE QUALITY
Paese: Switzerland

Interpretation of systemic interferon-alpha responses in classical swine fever infected naive and vaccinated animals

1. Role of interferon-alpha (IFN-a) responses in the pathogenesis of classical swine fever.
During the acute phase of the viral haemorrhagic disease classical swine fever (CSF) a severe haematological depletion in primary lymphoid organs and depletion of peripheral blood T and B lymphocytes is observed. The onset of these pathological events is before viraemia and independent of leukocyte infection indicating a host-mediated effect possibly through a "cytokine storm".

In this project, we have demonstrated that high serum levels of interferon-a (IFN-a) were found during this phase of CSF, detectable as early as 2 days post infection (p.i.), and reaching maximum levels 3-5 days p.i. This IFN-a response related to the virulence of the virus strain used, with avirulent virus not inducing any detectable serum IFN-a. A progressive depletion of natural interferon producing cells/plasmacytoid dendritic cells, the likely in vivo source of IFN-a, was also induced by the virus infection. An important finding was that the onset of severe lymphopenia was concomitant with the IFN-a responses, and all animals with serum IFN-a had depleted B and T lymphocytes. A statistically significant correlation between lymphocyte depletion and serum IFN-a indicates a relationship between the two events, which would be supported by the known haematological effects of high IFN-a doses in vivo.

An important element within these data is the relationship between the strength of the IFN-a response and the severity of the clinical outcome. This is pertinent not only to CSF, but also to other haemorrhagic fevers such as dengue fever, rift valley fever and South American haemorrhagic fevers. Some of these virus infections induce systemic IFN-a responses, which have been associated with severe disease. The known effect of IFN-a on the haematological system, the IFN receptor knockout studies in mice and the present study demonstrating the correlation between INF-a levels and lymphopenia suggest that an over-production of IFN-a during the acute phase of virus infection can lead to haematological disruption. Keeping the essential role of IFN-a in the innate immune response against virus infections in mind, a balanced regulation of IFN-a responses appears a critical element in the acute phase of certain haemorrhagic fevers, and would have therapeutical potential.

1. IFN-a responses in vaccinated pigs.
The analyses of serum IFN-a responses in naive and vaccinated immune animals would indicate that enhanced sensitisation for IFN-a responses operate in vivo. Our results show that at least 100-2000 less virus in the circulation of immune pigs induced 10-80% of the IFN-a found in the serum of naive pigs early post challenge. However, with highly immune pigs, for example after vaccination with the c-strain no IFN-a responses are detectable. This can be interpreted as a capacity of the vaccine to prevent virus replication. In this sense, the measuring of serum IFN-a after challenge infection of vaccinated pigs can serve as an indication of vaccine efficacy. Ideally, a vaccine would completely prevent the replication of the challenge virus and thus also prevent IFN-a responses.

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Artur SUMMERFIELD, (Head of Laboratory)
Tel.: +41-318489377
Fax: +41-318489222