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Avian infectious bursal disease (IBDV) or Gumboro disease, has a major economic impact on the poultry industry in France and worldwide. The causal agent is a burnavirus (a double-strand RNA virus) which causes anorexia, diarrhoea and tremor in 3 to 5-week old chicks and can result in mortality reaching 20 to 30% in affected farms. Because of the lesions which affect the bursa of Fabricius, surviving birds may present with severe immunodepression which favours the onset of infections, notably of a respiratory or digestive nature.

The vaccines available at present are not always effective because the recent epidemiology of IBDV has been marked by the regular emergence of viral strains which are able to develop in vaccinated animals. Some of these strains may be mutants that are not recognised by the antibodies generated by vaccination, thus reflecting antigenic drift of the virus. Others, such as the so-called "hypervirulent" variants, are endowed with the same antigenic signature as the vaccines but capable of multiplying very rapidly in a vaccinated animal. The molecular characterisation of field isolates, achieved by sequencing their genome, has enabled the identification of a domain of approximately 100 amino acids in the capsid protein (VP2) associated with virulence and antigenic drift of the virus. However, these results have not enabled elucidation of the molecular bases for viral antigenicity or an understanding of how a virus is or is not neutralised by an antibody.

For several years, the INRA Molecular Virology and Immunology Unit at Jouy-en-Josas has thus been seeking to characterise certain key steps in the viral cycle of IBDV (replicative system, morphogenesis and entry into the target cell) so as to better understand the pathogenicity of this virus and its interactions with a host. Determination of the atomic structure of the VP2 protein was one of the objectives of this work. This would allow us to identify both the specific amino acids involved in virulence and the residues associated with recognition of the cell to be infected and/or targets of the antibodies neutralising the virus. This work, coupled with data on the sequences of vaccine strains or field isolates, should clarify the antigenic drift of the virus so that vaccine strains which are better adapted to circulating strains can be developed in a rational manner.

For this purpose, scientists in this unit collaborated with the CNRS/INRA Joint Research Unit for Molecular and Structural Virology in Gif-sur-Yvette, using radiocrystallography to determine the three-dimensional structure of the VP2 viral capsid protein. Recently, this project has enabled determination of the tertiary structure of viral sub-particles of VP2 and complete viral particles of IBDV, at respective resolutions of 3 and 7 Å. More fundamentally, the results obtained have shown that the viral capsid of these double-strand RNA viruses only consists of one capsid protein which is endowed with a structure very similar to the capsid protein of RNA viruses with a positive polarity (nodaviruses, a poorly understand viral family which mainly infects insects) and the capsid protein of more complex double-strand RNA viruses (reoviridae such as the bluetongue virus or rotavirus).

However, this work has also thrown light on the antigenicity and virulence of viruses. It has shown that the use by hypervirulent strains of an alternative receptor on the lymphocyte surface is associated with two amino acids situated at the spike of VP2. These critical residues are surrounded by a crown of amino acids implicated in the antigenic drift of the virus. Thus only a few of the 440 residues of VP2 appear to control this immune response escape mechanism.

These results will thus permit the more rational production of VP2 antigen for vaccination, capable of inducing an adequate immune response to ensure effective protection against strains circulating in the field. These antigens could either be produced from live recombinant IBDV virus or in a particulate form, such as viral sub-particles of VP2, or expressed by a replicative vector such as an adenovirus or herpes virus.

Publication

The birnavirus crystal structure reveals new structural relationships among icosahedral viruses

Fasséli Coulibaly, Christophe Chevalier, Irina Gutsche, Joan Pous, Jorge Navaza, Stéphane Bressanelli, Bernard Delmas and Félix A. Rey.

Cell 2005. 120, 761-772.