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Virology

Host protein clips bird flu's wings in mammals

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The polymerase enzyme from avian influenza A viruses does not function well in human cells. The protein ANP32A has been identified as the cellular factor mediating a major component of this host restriction. See Letter p.101

Influenza A viruses circulate in diverse natural hosts, including mammalian and avian species. Yet transmission of these viruses 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. On page 101 of this issue, Long et al.1 report a breakthrough in understanding the restriction of avian influenza viruses in mammals.

The protein PB2 is a necessary component of the influenza A polymerase enzyme complex, which copies the viral genome and thus is essential for viral replication. For many years, researchers have known that a specific domain of PB2, the 627 domain, is involved in host restriction2. H5N1 strains and other 'bird flu' viruses rapidly acquire mutations in this domain following transmission to humans or inoculation of mammals in the laboratory3,4. These mutations, in turn, greatly enhance the growth, virulence and transmission of avian influenza A viruses in mammals5,6,7,8. Yet despite intense effort, the host factors and mechanisms that limit the functionality of non-mutated avian-adapted PB2 proteins in mammalian cells9,10,11,12,13,14 remained obscure.

Long et al. knew from previous work15 that the avian-adapted PB2 did not work well in mammalian cells because of the absence of a factor that enhances polymerase activity in avian cells, rather than because of the presence of an inhibitory factor in mammalian cells. To identify the missing positive factor, the authors used a panel of hybrid hamster cell lines that each carried a different fragment of the chicken genome. They expressed an avian-adapted PB2 protein, along with its essential viral partner proteins, in each cell line and measured the activity of the viral polymerase (Fig. 1). Out of 53 hybrid cell lines tested, four showed robust activity of the avian-adapted polymerase complex. By identifying the chicken genes that were shared by these four cell lines, Long et al. narrowed their search for the positive avian factor to just 12 genes. Then, by expressing each of the candidate genes singly in mammalian cells, the authors found what they were looking for: chicken ANP32A is a single gene that enables an avian-adapted PB2 protein to function efficiently in mammalian cells.

Figure 1: A cellular factor for host restriction.
figure1

The influenza virus's polymerase enzyme complex is essential for viral replication in a host cell. One component of this complex, the protein PB2, contributes to host restriction — the fact that avian-adapted viral polymerases do not function properly in mammalian cells. To identify the host protein that partners with PB2 to cause restriction, Long et al.1 used a panel of hybrid hamster–chicken cell lines, each containing a different region of the chicken genome. They expressed avian-adapted influenza polymerase in these cells and measured its activity; by comparing the chicken genomic components of cell lines with polymerase activity, the authors identified the host gene ANP32A as underlying host restriction of viral activity.

Confirmation that ANP32A protein supports influenza-polymerase activity was obtained by decreasing the expression of ANP32A in cells. When levels were reduced in chicken cells, the activity of an avian-adapted viral polymerase decreased. Similarly, when expression of the mammalian version of ANP32A was reduced in human cells, a human-adapted viral polymerase was less active. Thus, ANP32A is crucial for influenza A virus replication in both birds and mammals, but avian-adapted polymerases work inefficiently with mammalian ANP32A. These findings indicate that the adaptive changes that influenza viruses acquire in the PB2 627 domain following transmission to mammals allow the viral polymerase to partner with mammalian ANP32A.

The researchers report that chicken and human ANP32A proteins are similar except for a stretch of 33 amino acids that is missing from the human protein. All avian ANP32A genes, except those of ostriches and other ratites, encode these 33 amino acids, whereas all mammalian versions lack this region. Fittingly, addition of this sequence to a mammalian ANP32A protein was sufficient to permit avian-influenza PB2 function in mammalian cells. With this finding, what is known of bird flu in ostriches now makes perfect sense: influenza viruses isolated from ostriches tend to carry a PB2 with a mammalian-like sequence in the 627 domain16.

Long et al. have identified a host-cell protein that has an important function in the life cycle of influenza A viruses and that is a major factor in their host specificity. But it is still unclear how the virus uses ANP32A. The authors show that the protein does not alter the expression of PB2 nor its accumulation in the cell nucleus, where the viral genome is replicated. Is it instead directly involved in the replication of viral RNA? Relatively little is known about the host requirements for this step in the life cycle of the virus.

Investigating the precise relationship between PB2 and ANP32A will not only give insight into the mechanism of influenza host restriction, but may also trigger further discovery of virus–host interactions that contribute to viral RNA replication. Moreover, the influence of adaptation in the PB2 627 domain on viral fitness suggests that disrupting the virus–ANP32A interaction could be a powerful means of controlling influenza infection. Therefore, elucidation of ANP32A's role in virus replication in molecular detail may open the way to the development of new antiviral drugs.Footnote 1

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Correspondence to Anice C. Lowen.

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Influenza: Pathways to human adaptation

Virology: Bird flu in mammals

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Lowen, A. Host protein clips bird flu's wings in mammals. Nature 529, 30–31 (2016). https://doi.org/10.1038/529030a

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