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Multiple routes of invasion of wild-type Clade 1 highly pathogenic avian influenza H5N1 virus into the central nervous system (CNS) after intranasal exposure in ferrets

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Abstract

Human infections with highly pathogenic avian influenza (HPAI) H5N1 have been associated with central nervous system involvement. The purpose of this study was to examine the route of invasion of wild-type HPAI H5N1 virus into the central nervous system (CNS) using a ferret model of infection. Sixteen ferrets were exposed by the intranasal route to 106 TCID50 of A/Vietnam/1203/04, a Clade 1 strain originally isolated from a fatal human case. The ferrets were euthanased for histological and virological analysis at intervals after challenge at 1, 3, 5, 6 and 7 days post-inoculation (dpi). From 5 dpi encephalitis was seen in all examined ferrets. The detection of antigen in the olfactory epithelium, the olfactory bulb, and related nuclei, in that temporal sequence, supported the contention that this is a major infection route for this virus strain. The detection of antigen in the epithelial cells in the Eustachian tube on 1 dpi, followed by the cochlea and vestibulocochlear nerve on 5 dpi is consistent with a second anterograde route of invasion, namely the vestibulocochlear pathway. There was also antigen in the lining of the ventricles and central canal indicating spread via the cerebrospinal fluid. However, evidence for haematogenous dissemination in the form of antigen in the brain parenchyma surrounding blood vessels was not found. This study provides support to the contention that wild-type HPAI H5N1 virus strains may enter the CNS via cranial nerve pathways and that the ferret is an appropriate model to study preventive and therapeutic procedures involving neural infection with these viruses by this route.

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Acknowledgments

This work was supported in part by a visiting fellowship program of National Agriculture and Food Research Organization (NARO), Japan. The work was conducted in the laboratories of CSIRO Livestock Industries at the Australian Animal Health Laboratory, Geelong, Victoria.

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Authors and Affiliations

  1. National Institute of Animal Health, Kannondai, Tsukuba, Ibaraki, 305-0856, Japan

    Manabu Yamada

  2. Australian Animal Health Laboratory, CSIRO Livestock Industries, PO Bag 24, 5 Portarlington Road, Geelong, VIC, 3220, Australia

    Manabu Yamada, John Bingham, Jean Payne, Jennifer Rookes, Suzanne Lowther, Jessica Haining, Rachel Robinson, Dayna Johnson & Deborah Middleton

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  1. Manabu Yamada
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Correspondence to Manabu Yamada.

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Yamada, M., Bingham, J., Payne, J. et al. Multiple routes of invasion of wild-type Clade 1 highly pathogenic avian influenza H5N1 virus into the central nervous system (CNS) after intranasal exposure in ferrets. Acta Neuropathol 124, 505–516 (2012). https://doi.org/10.1007/s00401-012-1010-8

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  • DOI: https://doi.org/10.1007/s00401-012-1010-8

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