Investigating the role of ANP32A in the replication of Avian Influenza Virus

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Influenza viruses infect domestic animals including poultry and pigs, causing loss of income, social and economic disruption. Avian influenza remains one of the major threats to food security. Adaptation of avian influenza in animal hosts leads to viruses that are transmitted in humans and carries the risk of driving emergent influenza pandemics. We have investigated a family of host proteins, ANP32, that are co-opted by influenza virus to support its replication. The difference between ANP32A in chickens and mammalian hosts accounts for one of the host range barriers that protect pigs and humans from zoonotic infections by avian influenza viruses. Avian influenza virus RNA-dependent RNA polymerase is unable to utilise the mammalian ANP32A protein unless it adapts by mutation of the viral PB2 protein. We have previously shown that the form of the protein ANP32A present in flighted birds differs from that in mammals due to presence of an additional exon encoding 33 amino acids that contribute to the mature protein. We have preliminary data suggesting that removal of this exon reduces or avian influenza virus replication in chicken cells. We will identify the specific regions of ANP32A needed for viral protein interactions. We will use new genome editing tools that we have developed to modify chicken cells to test our predictions of which targeted changes to ANP32A will have the most significant effect on avian influenza virus replication. We will generate a series of mutations of ANP32A and test their effects on avian influenza polymerase function and virus replication. We will determine any global changes in the RNA transcriptome of the edited cells containing modified ANP32A protein. We will investigate the function of ANP32A in genome edited animals. This information will inform control strategies for protection of commercial poultry from AIV infection. It will also be of interest to researchers studying influenza virus in humans and livestock.