Influenza A viruses circulate in various natural hosts, including mammals and birds. Transmission of influenza virus between mammals and birds occurs only rarely, owing to host restriction: an influenza A virus that is adapted to an avian host typically does not grow well in a mammalian host, and vice versa. When such restrictions are overcome and an avian virus transmits to humans, a pandemic can occur.
The Influenza PB2 protein is part of the influenza A polymerase enzyme complex, which copies the virus genome and is essential for replication. For many years, researchers have known that a specific domain of PB2 is involved in host restriction. A new paper in Nature (£) shows that a single bird gene, ANP32A, enables an avian-adapted PB2 protein to function efficiently in mammalian cells. Chicken and human ANP32A proteins are similar except for a stretch of 33 amino acids missing from the human protein. All avian ANP32A genes, except those of ostriches, encode these 33 amino acids, whereas all mammalian versions lack this region.
Further investigation of ANP32A’s role in virus replication may open the way to the development of new antiviral drugs.
Species difference in ANP32A underlies influenza A virus polymerase host restriction. (2016) Nature 529, 101–104 doi:10.1038/nature16474
Influenza pandemics occur unpredictably when zoonotic influenza viruses with novel antigenicity acquire the ability to transmit amongst humans. Host range breaches are limited by incompatibilities between avian virus components and the human host. Barriers include receptor preference, virion stability and poor activity of the avian virus RNA-dependent RNA polymerase in human cells. Mutants of the heterotrimeric viral polymerase components, particularly PB2 protein, are selected during mammalian adaptation, but their mode of action is unknown. We show that a species-specific difference in host protein ANP32A accounts for the suboptimal function of avian virus polymerase in mammalian cells. Avian ANP32A possesses an additional 33 amino acids between the leucine-rich repeats and carboxy-terminal low-complexity acidic region domains. In mammalian cells, avian ANP32A rescued the suboptimal function of avian virus polymerase to levels similar to mammalian-adapted polymerase. Deletion of the avian-specific sequence from chicken ANP32A abrogated this activity, whereas its insertion into human ANP32A, or closely related ANP32B, supported avian virus polymerase function. Substitutions, such as PB2(E627K), were rapidly selected upon infection of humans with avian H5N1 or H7N9 influenza viruses, adapting the viral polymerase for the shorter mammalian ANP32A. Thus ANP32A represents an essential host partner co-opted to support influenza virus replication and is a candidate host target for novel antivirals.