Abstract
Transmission of avian influenza viruses from bird to human is a rare event even though avian influenza viruses infect the ciliated epithelium of human airways in vitro and ex vivo. Using an in vitro model of human ciliated airway epithelium (HAE), we demonstrate that while human and avian influenza viruses efficiently infect at temperatures of the human distal airways (37°C), avian, but not human, influenza viruses are restricted for infection at the cooler temperatures of the human proximal airways (32°C). These data support the hypothesis that avian influenza viruses, ordinarily adapted to the temperature of the avian enteric tract (40°C), rarely infect humans, in part due to differences in host airway regional temperatures. Previously, a critical residue at position 627 in the avian influenza virus polymerase subunit, PB2, was identified as conferring temperature-dependency in mammalian cells. Here, we use reverse genetics to show that avianization of residue 627 attenuates a human virus, but does not account for the different infection between 32°C and 37°C. To determine the mechanism of temperature restriction of avian influenza viruses in HAE at 32°C, we generated recombinant human influenza viruses in either the A/Victoria/3/75 (H3N2) or A/PR/8/34 (H1N1) genetic background that contained avian or avian-like glycoproteins. Two of these viruses, A/Victoria/3/75 with L226Q and S228G mutations in hemagglutinin (HA) and neuraminidase (NA) from A/Chick/Italy/1347/99 and A/PR/8/34 containing the H7 and N1 from A/Chick/Italy/1347/99, exhibited temperature restriction approaching that of wholly avian influenza viruses. These data suggest that influenza viruses bearing avian or avian-like surface glycoproteins have a reduced capacity to establish productive infection at the temperature of the human proximal airways. This temperature restriction may limit zoonotic transmission of avian influenza viruses and suggests that adaptation of avian influenza viruses to efficient infection at 32°C may represent a critical evolutionary step enabling human-to-human transmission.
Highlights
Influenza viruses circulating in the human population are predominately type A and B, with type A being more common [1]
Since the avian virus isolates used in these experiments are neither derived from samples obtained from humans nor passaged in human cells in vitro, we investigated whether growth attenuation at low temperatures would be retained in a highly pathogenic H5N1 (A/VN/1203/04) influenza virus isolated from a fatal human case [34]
We suggest that while the warmer temperatures of the distal airways enable comparable infection by both human and avian influenza viruses, the cooler temperatures of the human proximal airways only support efficient and robust infection of the ciliated airway epithelium by human influenza viruses
Summary
Influenza viruses circulating in the human population are predominately type A and B, with type A being more common [1]. Still, documented evidence of transmission of avian influenza viruses directly from birds to humans is rare, partly because species barriers restrict avian influenza virus infection of the epithelial cells of the human respiratory tract, the primary site of influenza virus infection and spread. Recent reports have detected significant levels of a2,3 SA on human airway epithelium both in vitro and ex vivo, including in nasopharyngeal and tracheobronchial tissue [11,12,13,14]. This SA distribution correlated with avian influenza virus infection in vitro and ex vivo and raised the possibility that avian viruses could infect the upper airways in vivo. It is universally accepted that human-to-human transmission of avian influenza viruses requires adaptation of HA to switch from a2,3 to a2,6 SA usage, the cumulative data published to date indicate that SA linkages and Author Summary
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