Abstract
Influenza A viruses (IAVs) cause seasonal epidemics and occasional pandemics. Most pandemics occurred upon adaptation of avian IAVs to humans. This adaptation includes a hallmark receptor-binding specificity switch of hemagglutinin (HA) from avian-type α2,3- to human-type α2,6-linked sialic acids. Complementary changes of the receptor-destroying neuraminidase (NA) are considered to restore the precarious, but poorly described, HA-NA-receptor balance required for virus fitness. In comparison to the detailed functional description of adaptive mutations in HA, little is known about the functional consequences of mutations in NA in relation to their effect on the HA-NA balance and host tropism. An understudied feature of NA is the presence of a second sialic acid-binding site (2SBS) in avian IAVs and absence of a 2SBS in human IAVs, which affects NA catalytic activity. Here we demonstrate that mutation of the 2SBS of avian IAV H5N1 disturbs the HA-NA balance. Passaging of a 2SBS-negative H5N1 virus on MDCK cells selected for progeny with a restored HA-NA balance. These viruses obtained mutations in NA that restored a functional 2SBS and/or in HA that reduced binding of avian-type receptors. Importantly, a particular HA mutation also resulted in increased binding of human-type receptors. Phylogenetic analyses of avian IAVs show that also in the field, mutations in the 2SBS precede mutations in HA that reduce binding of avian-type receptors and increase binding of human-type receptors. Thus, 2SBS mutations in NA can drive acquisition of mutations in HA that not only restore the HA-NA balance, but may also confer increased zoonotic potential.
Highlights
Influenza A viruses (IAVs) cause seasonal epidemics as well as occasional pandemics
Influenza pandemics can have devastating effects as was dramatically demonstrated by the so-called Spanish flu in 1918. Such pandemics are caused by animal influenza A viruses (IAVs) that are sufficiently adapted to humans
We previously generated an H5N1 virus with mutation K432E in the 2SBS of NA (H5N1432E) [5] to analyze the importance of the 2SBS for NA catalytic activity and virus replication. This mutation, which reduced catalytic activity of NA on multivalent, but not monovalent substrates [5], resulting from reduced receptor binding via the 2SBS (S1 Fig), rapidly reverted back to wild type NA (432K)[5]. This observation prompted us to examine the effect of mutation K432E in NA on the HA-NA balance of H5N1 virus
Summary
Influenza A viruses (IAVs) cause seasonal epidemics as well as occasional pandemics. The latter occur when animal viruses cross the host species barrier and adapt to humans. Human viruses prefer binding to α2,6-linked SIA (α2,6 SIA; human-type receptor) expressed on human upper airway epithelia whereas most avian viruses prefer binding to α2,3-linked SIA (α2,3 SIA; avian-type receptor) present on bird intestinal epithelia [1]. Some avian viruses, such as recent H7N9 and H9N2 viruses, can bind to α2,6 SIA [2, 3] and are regarded as viruses with increased zoonotic potential. What drives the selection of mutations in HA resulting in the binding of human-type receptors in these avian viruses is, not understood
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