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Summary Avian influenza A viruses rarely infect humans, but if they do and transmit among them, worldwide outbreaks (pandemics) can result. The recent sporadic infections of humans in China with a previously unrecognized avian influenza A virus of the H7N9 subtype (A(H7N9)) have caused concern due to the appreciable case fatality rate associated with these infections (>25%), potential instances of human-to-human transmission1, and the lack of pre-existing immunity among humans to viruses of this subtype. Here, we therefore characterized two early human A(H7N9) isolates, A/Anhui/1/2013 and A/Shanghai/1/2013 (H7N9; hereafter referred to as Anhui/1 and Shanghai/1, respectively). In mice, Anhui/1 and Shanghai/1 were more pathogenic than a control avian H7N9 virus (A/duck/Gunma/466/2011; H7N9; Dk/GM466) and a representative pandemic 2009 H1N1 virus (A/California/04/2009; H1N1; CA04). Anhui/1, Shanghai/1, and Dk/GM466 replicated well in the nasal turbinates of ferrets. In nonhuman primates (NHPs), Anhui/1 and Dk/GM466 replicated efficiently in the upper and lower respiratory tracts, whereas the replicative ability of conventional human influenza viruses is typically restricted to the upper respiratory tract of infected primates. By contrast, Anhui/1 did not replicate well in miniature pigs upon intranasal inoculation. Most critically, Anhui/1 transmitted via respiratory droplets in one of three pairs of ferrets. Glycan arrays demonstrated that Anhui/1, Shanghai/1, and A/Hangzhou/1/2013 (a third human A(H7N9) virus tested in this assay) bind to human virus-type receptors, a property that may be critical for virus transmissibility in ferrets. Anhui/1 was less sensitive than a pandemic 2009 H1N1 virus to neuraminidase inhibitors, although both viruses were equally susceptible to an experimental antiviral polymerase inhibitor. The robust replicative ability in mice, ferrets, and NHPs and the limited transmissibility in ferrets of Anhui/1 suggest that A(H7N9) viruses have pandemic potential.

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Many enveloped viruses induce multinucleated cells (syncytia), reflective of membrane fusion events caused by the same machinery that underlies viral entry. These syncytia are thought to facilitate replication and evasion of the host immune response. Here, we report that co-culture of human cells expressing the receptor ACE2 with cells expressing SARS-CoV-2 spike, results in synapse-like intercellular contacts that initiate cell-cell fusion, producing syncytia resembling those we identify in lungs of COVID-19 patients. To assess the mechanism of spike/ACE2-driven membrane fusion, we developed a microscopy-based, cell-cell fusion assay to screen ~6000 drugs and >30 spike variants. Together with quantitative cell biology approaches, the screen reveals an essential role for biophysical aspects of the membrane, particularly cholesterol-rich regions, in spike-mediated fusion, which extends to replication-competent SARS-CoV-2 isolates. Our findings potentially provide a molecular basis for positive outcomes reported in COVID-19 patients taking statins and suggest new strategies for therapeutics targeting the membrane of SARS-CoV-2 and other fusogenic viruses.