Species specific differences in use of ANP32 proteins by influenza A virus

• Published in: eLife Vol. 8
• Main Authors: Long, Jason S, Idoko-Akoh, Alewo, Mistry, Bhakti, Goldhill, Daniel, Staller, Ecco, Schreyer, Jocelyn, Ross, Craig, Goodbourn, Steve, Shelton, Holly, Skinner, Michael A, Sang, Helen, McGrew, Michael J, Barclay, Wendy
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 04.06.2019; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Amino acids; Animals; ANP32A; ANP32B; Antiviral agents; Antiviral drugs; Avian influenza; Avian influenza viruses; Cell Line; Cells (Biology); Chickens; CRISPR; Epidemics; gene editing; Genes; Genomes; Genomics; Host range; Host Specificity; Host-Pathogen Interactions; Host-virus relationships; Humans; Infections; Influenza; Influenza A; Influenza A virus - enzymology; Influenza A virus - growth & development; Influenza viruses; Insects; Mammals; Microbiology and Infectious Disease; Nuclear Proteins - metabolism; Pandemics; Phosphoproteins; Phylogenetics; Physiological aspects; polymerase; Proteins; RNA polymerase; RNA-Binding Proteins - metabolism; RNA-Dependent RNA Polymerase - metabolism; Species (Biology); Virus Replication; Viruses; United Kingdom; United Kingdom > UK; chicken; ANP32A; infectious disease; Influenza; polymerase; microbiology; ANP32B; gene editing; human; virus
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.45066

Influenza A viruses (IAV) are subject to species barriers that prevent frequent zoonotic transmission and pandemics. One of these barriers is the poor activity of avian IAV polymerases in human cells. Differences between avian and mammalian ANP32 proteins underlie this host range barrier. Human ANP32A and ANP32B homologues both support function of human-adapted influenza polymerase but do not support efficient activity of avian IAV polymerase which requires avian ANP32A. We show here that the gene currently designated as avian ANP32B is evolutionarily distinct from mammalian ANP32B, and that chicken ANP32B does not support IAV polymerase activity even of human-adapted viruses. Consequently, IAV relies solely on chicken ANP32A to support its replication in chicken cells. Amino acids 129I and 130N, accounted for the inactivity of chicken ANP32B. Transfer of these residues to chicken ANP32A abolished support of IAV polymerase. Understanding ANP32 function will help develop antiviral strategies and aid the design of influenza virus resilient genome edited chickens. The influenza A virus pandemic of 1918 killed more people than the armed conflicts of World War 1. Like all other pandemic and seasonal influenza, this virus originated from bird viruses. In fact, avian influenza viruses continually threaten to spark new outbreaks in humans, but pandemics do not occur often. This is because these viruses must undergo several adaptations before they can replicate in and spread between people. Viruses make new copies of themselves using the molecular machinery of the cells that they invade. The proteins that make up this machinery are often slightly different in different species, and so a virus that can replicate in cells of one species might not be able to do so when it invades a cell from another species. In 2016, researchers discovered that species differences in a cell protein called ANP32A pose a key barrier that avian influenza viruses have to overcome. Now, Long et al. – including some of the researchers involved in the 2016 study – show that the avian influenza virus cannot replicate in chicken cells that lack ANP32A. Exploring closely related versions of the genes that produce ANP32A and its relative ANP32B in different species revealed the region of the protein that the virus relies on to support its replication. Long et al. speculate that by making a few small changes to the ANP32A gene in chickens, it might be possible to generate a gene-edited chicken that is resilient to influenza. Close contact with poultry has led to hundreds of cases of ‘bird ‘flu’ in South East Asia, many of which have been fatal. Moreover, if avian influenza viruses mutate further in an infected person, a new pandemic could begin. Stopping influenza viruses from replicating in chickens would prevent people from being exposed to these dangerous viruses, whilst also improving the welfare of the chickens.