Unlike in mammals, where influenza viruses generally produce a respiratory infection, influenza in birds is a gastrointestinal malady. The virus attaches to - and replicates in – the avian gut, and is spread primarily through infected droppings.
As you might imagine, avian flu viruses are well adapted to attack the kind of cells found within the avian intestinal tract; α2,3-linked sialic acid avian receptor cells.
Humans, and many (but not all) mammals have very few α2,3 receptor cells in their upper airway (but do have some deep in the lungs), making it difficult for avian flu viruses to easily attach to, and infect, non-avian species.
When they do jump to humans, it usually results in a serious deep lung infection (pneumonia).
Human, or mammalian adapted flu viruses bind preferentially to a different type of cell - α2,6 receptor cells - which are abundant in their upper respiratory systems. They are also adapted to replicate in the 5 to 10 degree cooler environment of the upper airway, compared to the intestinal tract of birds.
For an avian influenza virus to successfully jump species and to become a human pandemic threat, these receptor binding and temperature tolerance issues are believed to be two of the biggest hurdles. There are likely others, but these two appear to top the list.
As avian viruses jump (even tentatively) to other species, it gives them a chance to produce host adaptations; mutations that favor survival in their new environment. The more jumps, the more opportunities the virus has (through trial and error) to `figure out’ what evolutionary changes are needed to make the new species a suitable host.
Viruses also change slowly through antigenic drift, even in their native hosts, and can abruptly change through antigenic shift – or reassortment. Shift occurs when two flu viruses inhabit the same host at the same time, swap genetic material, and produce a `hybrid’ strain.
Birds, swine, humans . . . in fact almost any flu susceptible species – can act as a mixing vessel. While pandemic viruses are rare, as any virologist will tell you . . . Shift happens.
While we are justifiably concerned over the recently emerged H7N9 virus given its track record over the past couple of years, the avian flu virus with the longest resume and greatest diversity is H5N1 and its recently emerged cousins; H5N8, H5N6, H5N3. This virus has been around for 18 years, and has gone from a single clade discovered in 1996 to a diverse, and growing constellation of clades, sub-clades, and variants within sub-clades.
The following chart from the World Health Organization hints at just how much diversity the virus acquired over its first 15 years..
(click to load larger image) (Note: Chart only goes through 2011)
Until a year or so ago, most H5N1 clades were classified by 3 digit identifiers, such a clade 2.3.4.
But in 2013, researchers reported on Novel Variants of Clade 2.3.4 Highly Pathogenic Avian Influenza A(H5N1) Viruses, China, and suggested that `these groups should be assigned new fourth-order clades of 22.214.171.124, 126.96.36.199, and 188.8.131.52 to reflect the wide divergence of clade 2.3.4 viruses.’
In short order, we saw the emergence of several new H5 subtypes (through reassortment), all carrying the newly identified H5 clade 184.108.40.206 HA gene segment, including the recent high flying H5N8 and H5N6 subtypes. The graphic below (produced before H5N8 showed up in Europe and North America) illustrates their recent geographic spread in Asia comes from the November FAO-EMPRES Report On The Emergence And Threat Of H5N6).
While there are a lot of H5 clades out there, and more will invariably appear, right now clade 220.127.116.11 is making a lot of noise. So the open access study, published this week in the Journal Veterinary Research, that looks at the receptor binding qualities of this new clade is of particular interest.
While many will want to read the entire report, I’ve excepted some highlights below.
In short, they determined that this new clade binds to both avian α2,3 and mammalian α2,6 receptor cells, and that at least one (of 4 tested) strains replicated well, and transmitted efficiently, in test guinea pigs.
The emerging H5 clade 18.104.22.168 viruses of different NA subtypes have been detected in different domestic poultry in China. We evaluated the receptor binding property and transmissibility of four novel H5 clade 22.214.171.124 subtype highly pathogenic avian influenza viruses. The results show that these viruses bound to both avian-type (α-2,3) and human-type (α-2,6) receptors. Furthermore, we found that one of these viruses, GS/EC/1112/11, not only replicated but also transmitted efficiently in guinea pigs. Therefore, such novel H5 subtype viruses have the potential of a pandemic threat.
Historically, changes in the receptor binding protein of influenza virus, HA, have been implicated in the initiation of a pandemic. It has been established for the H1N1 (1918), H2N2 (1957) and H3N2 (1968) pandemic viruses that a change in HA protein from a preference for α-2,3-linked sialic acids (avian receptor) to a preference for α-2,6-linked sialic acids (human receptor) is a prerequisite for efficient transmission of avian viruses to humans .
H5 HPAIV pose a serious pandemic threat due to their virulence and high mortality in humans, and their increasingly expanding host reservoir and significant ongoing evolution could enhance their human-to-human transmissibility. Recently, novel clade 126.96.36.199 H5 HPAIV with various NA subtypes (H5N1, H5N2, H5N6, and H5N8) were reported in Eastern China and South Korea -,,.
Here, we evaluated their receptor specificity and transmission in guinea pigs. The results show that the viruses bound to both avian-type (α-2,3) and human-type (α-2,6) receptors. In humans, the α-2,6 receptor is expressed mainly in the upper airway, while the α-2,3 receptor is expressed in alveoli and the terminal bronchiole .
A virus with good affinity to both α-2,3 and α-2,6 receptors may especially be harmful, as it could infect efficiently via its binding to α-2,6 receptors in the upper airway and simultaneously cause severe infection in the lung via its binding to α-2,3 receptors. And this hypothesis is supported by the fact that one of the two well-characterized HA genes from the H1N1 1918 pandemic virus binds efficiently to both α-2,3 and α-2,6 receptors . In addition, previous studies showed that the human-infecting novel H7N9 and the latest reassortant H10N8 avian influenza viruses yet have substantial affinity to both avian-type (α-2,3) and human-type (α-2,6) receptors ,.
Sequence analysis showed that novel H5 (HPAIV) clade 188.8.131.52 simultaneously carry a T160A mutation which results in the lack of an oligosaccharide side chain at 158–160 of HA, and it is critical for the H5 subtype influenza viruses tested to bind to human-like receptors and to transmit among a mammalian host ,. Whether this T160A variation affects the receptor-binding property deserves further investigation.
Previous studies showed that some H5 subtype influenza viruses can transmit efficiently in guinea pigs . In this study, we also found that one of these viruses, GS/EC/1112/11, not only replicated but also transmitted efficiently in guinea pigs. These findings emphasize that continued circulation of these viruses may pose health threats for humans. Therefore, we need to intensify our effort to detect such viruses as early as possible.
Although there are likely other inhibiting factors stopping this H5 clade 184.108.40.206 strain (and others) from sparking a pandemic, this dual binding ability would appear to move this particular clade a little closer towards it becoming a potential global health threat.
That said, it should be noted that in 2013 we saw a similar finding with the H7N9 virus (see NEJM Journal Watch: Characteristics of H7N9), but that virus still has not displayed the ability to spread efficiently from human-to-human.
Despite our continual gains in knowledge regarding influenza viruses, we obviously don’t know all of the factors involved in turning an avian influenza virus into a `humanized’ one. But studies like this one may help us recognize an impending threat, and give us enough warning time to prepare our defenses (i.e. vaccines, antivirals, etc.).
For more on the evolution of H5 and H7 viruses, you might wish to revisit: