Complete-proteome mapping of human influenza A adaptive mutations: implications for human transmissibility of zoonotic strains.
BACKGROUND
There is widespread concern that H5N1 avian influenza A viruses will emerge as a pandemic threat, if they become capable of human-to-human (H2H) transmission. Avian strains lack this capability, which suggests that it requires important adaptive mutations. We performed a large-scale comparative analysis of proteins from avian and human strains, to produce a catalogue of mutations associated with H2H transmissibility, and to detect their presence in avian isolates.


RESULTS
We constructed a dataset of influenza A protein sequences from 92,343 public database records. Human and avian sequence subsets were compared, using a method based on mutual information, to identify characteristic sites where human isolates present conserved mutations. The resulting catalogue comprises 68 characteristic sites in eight internal proteins. Subtype variability prevented the identification of adaptive mutations in the hemagglutinin and neuraminidase proteins. The high number of sites in the ribonucleoprotein complex suggests interdependence between mutations in multiple proteins. Characteristic sites are often clustered within known functional regions, suggesting their functional roles in cellular processes. By isolating and concatenating characteristic site residues, we defined adaptation signatures, which summarize the adaptive potential of specific isolates. Most adaptive mutations emerged within three decades after the 1918 pandemic, and have remained remarkably stable thereafter. Two lineages with stable internal protein constellations have circulated among humans without reassorting. On the contrary, H5N1 avian and swine viruses reassort frequently, causing both gains and losses of adaptive mutations.


CONCLUSIONS
Human host adaptation appears to be complex and systemic, involving nearly all influenza proteins. Adaptation signatures suggest that the ability of H5N1 strains to infect humans is related to the presence of an unusually high number of adaptive mutations. However, these mutations appear unstable, suggesting low pandemic potential of H5N1 in its current form. In addition, adaptation signatures indicate that pandemic H1N1/09 strain possesses multiple human-transmissibility mutations, though not an unusually high number with respect to swine strains that infected humans in the past. Adaptation signatures provide a novel tool for identifying zoonotic strains with the potential to infect humans.
Centre for Genomics and Global Health, University of Oxford, Oxford, United Kingdom. olivo.miotto@ndm.ox.ac.uk
Olivo
O
Miotto
A T
AT
Heiny
Randy
R
Albrecht
Adolfo
A
García-Sastre
Tin Wee
TW
Tan
J Thomas
JT
August
Vladimir
V
Brusic
D000222:Adaptation, Physiological / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001717:Birds; D030562:Databases, Protein; D006736:Horses; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics / Q000378:metabolism; D009980:Influenza A virus / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D005585:Influenza in Birds / Q000635:transmission / Q000821:virology; D007251:Influenza, Human / Q000635:transmission / Q000821:virology; D008969:Molecular Sequence Data; D009154:Mutation; D009976:Orthomyxoviridae Infections / Q000635:transmission / Q000821:virology; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D017386:Sequence Homology, Amino Acid; D013552:Swine; D013997:Time Factors; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism; D015047:Zoonoses / Q000821:virology
D020543:Proteome; D014764:Viral Proteins