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In vivo and in vitro characterization of neurotropism of highly pathogenic influenza virus H5N8 (clade 2.3.3.4b) in chicken and duck
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International audience. In birds, avian influenza A viruses cause a wide variety of clinical signs. Due to their polybasic cleavage site recognized by ubiquitous proteases, highly pathogenic avian influenza A viruses (HPAIV) replicate systemically, causing significant tissue damage which may involve severe Central Nervous System (CNS) injury.H5Nx HPAIV of clade 2.3.4.4b, in particular subtype H5N8, caused devastating epizootics in recent years, particularly in Europe. In farms, infection by the H5N8 virus in 2016 was associated with severe neurological disorders in the majority of ducks, whereas these were almost non-existent in chickens.The objective of this project was to characterize the infection and the host response at the CNS level to better understand this difference in neuropathology between the two species. For this purpose, two models were used: animal experimental infection and primary cortical neurons culture.Experimental infection with H5N8 HPAIV indeed showed predominant neurological involvement in ducks whereas chickens were mainly affected by respiratory distress. RT-PCR and immunohistochemistry revealed that viral replication was early and intense in duck brains while brain colonization occurred at later stages of infection in chickens. Accordingly duck brain histological lesions were more severe compared to chickens. Analyses of the host response in the brain showed intense and prolonged innate immune and inflammatory responses in ducks which was absent in the early stages of infection in chickens.In order to determine if the origin of the difference in neurological damage was due to a better sensitivity of duck neurons, we developed a culture model of primary avian neurons. Infection kinetics revealed equivalent permissiveness and sensitivity to H5N8 virus in both species. In contrast to in vivo observations, expression of innate immunity and inflammatory genes was similar in chicken and duck neurons.In conclusion, as the virus seems to replicate more efficiently in ducks, viral loads are very rapidly elevated and colonisation of the brain is early. Viral replication in the duck CNS therefore takes place over several days, giving the virus time to cause significant tissue damages.
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