Since May 2014, highly pathogenic avian influenza H5N6 virus has been reported to cause six severe human infections three of which were fatal. The biological properties of this subtype, in particular its relative pathogenicity and transmissibility in mammals, are not known. We characterized the virus receptor-binding affinity, pathogenicity, and transmissibility in mice and ferrets of four H5N6 isolates derived from waterfowl in China from 2013-2014. All four H5N6 viruses have acquired a binding affinity for human-like SA␣2,6Gal-linked receptor to be able to attach to human tracheal epithelial and alveolar cells. The emergent H5N6 viruses, which share high sequence similarity with the human isolate A/Guangzhou/39715/2014 (H5N6), were fully infective and highly transmissible by direct contact in ferrets but showed less-severe pathogenicity than the parental H5N1 virus. The present results highlight the threat of emergent H5N6 viruses to poultry and human health and the need to closely track their continual adaptation in humans. O n 7 May 2014, the Chinese National Health and Family Planning Commission (NHFPC) announced the first human case of avian H5N6 influenza virus infection (1). Subsequently, three more human infections with H5N6 virus cases were reported in the winter of 2014-2015 (2, 3). Between 30 December 2015 and 2 January 2016, the NHFPC notified the World Health Organization of two additional human cases of avian H5N6 virus infection. All six human infections were presented as acute respiratory distress syndrome (ARDS) of which three were fatal. Five cases had a common history of contact with or exposure to poultry or livebird markets before disease onset (1-3), suggesting zoonotic transmission. Sequence analyses of the human H5N6 isolates indicated that the virus was derived from clade 2.3.4.4 avian H5N6 viruses that are circulating in poultry in China (1, 2, 4). Avian H5N6 influenza virus was first isolated from mallards in North America in 1975 (5). In China, H5N6 virus first emerged in 2010 and has since been extensively circulating in both domestic and wild birds (6-9). Recent surveillance data from the Ministry of Agriculture of China indicate that H5N6 viruses have become enzootic in domestic poultry. Unlike the worldwide distribution H5N2 and H5N8 viruses (10-12), prevailing H5N6 viruses appear to be largely confined to China and Laos (13). We recently characterized the novel H5N6 viruses in poultry (14); however, their zoonotic capability and characteristics are poorly understood. In the present study, we examined the emergent H5N6 virus for its genetic characteristics, receptor binding properties, pathogenicity, and transmissibility in mice and ferrets. MATERIALS AND METHODS Ethical

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