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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.
Methodology/Principal Findings
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.
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- Feed: PLoS ONE Alerts: Molecular Biology
- Original article
