Wednesday, August 15, 2018

Sci. Repts.: Characterization Of Avian Influenza Virus Attachment Patterns To Human & Pig Tissues


RBD's or receptor binding domains, are that part of the virus that allows it to attach to receptor cells in a host's body. Different viruses are attracted to different types of cells, which explains why some viruses that affect man, don't affect other species, and why we don't get influenza in our elbow or thumb.

Receptor cells have stalks of sugar (carbohydrate) molecules on their surface. These carbohydrate molecules - called `glycans' - form a dense sugary coating to all animal cell membranes. The composition of these stalks varies between types of cells and hosts, but the right combination can provide attachment points for some types of viruses.
When the right virus meets a compatible receptor cell, they bind, and assuming there are no other barriers in place, infection can ensue. 
Avian influenza viruses, like H7N9 and H5N1, bind preferentially to the alpha 2,3 receptor cells found in the gastrointestinal tract of birds, while `humanized’ flu viruses - like H3N2 and H1N1 - have an affinity for the alpha 2,6 receptor cells most commonly found in the human respiratory system. 
While greatly outnumbered by alpha 2,6 receptor cells, humans do have some of these avian-like alpha 2,3 receptor cells, which probably explains why some avian viruses have jumped directly to humans.
There are certainly other factors involved in a successful infection.  For example, avian flu viruses tend to replicate better at the higher temperatures found in the gastrointestinal tract of birds, rather than those present in the upper airway of humans.
But host adaptation mutations - like the PB2 E627K amino acid substitution - enable influenza viruses to replicate at lower temperatures (roughly 33C).
And we've seen growing evidence of avian viruses developing HA G186V and Q226L/I amino acid substitutions, which are linked to switching the virus from binding preferentially to avian (a2,3) receptor cells to mammalian (a2,6) receptor cells (see Cell: Avian-to-Human Receptor-Binding Adaptation by Influenza A Virus Hemagglutinin H4).

Despite these adaptations, human infection by avian influenza viruses remains relatively uncommon, while pigs - which carry both alpha 2,6 alpha 2,3 receptor cells - are susceptible to a wide variety of human, swine, and avian flu viruses and are viewed as likely `mixing vessels' for influenza. 

Which begs the question: Do avian viruses require an intermediate (i.e. swine) host in order to jump to humans?
Attempting to answer this, we have a lengthy and quite detailed study - published today in Scientific Reports - where researchers using four different AIVs (Mallard H3N2, Mallard H6N1, Ruddy Turnstone H12N5, and Black Headed Gull H16N2) explored their ability to bind to a variety of human and pig tissues.
The answer they reveal is, while pigs are indeed susceptible to many avian viruses, in general `. . . . AIV attachment was more abundant to human tissues than to pig tissues.'

The full report is available at the link below, and I can't possibly do it justice here, so follow the link to read it in its entirety.   I've excerpted the abstract, and some sections from the discussion below:
Characterization of avian influenza virus attachment patterns to human and pig tissues 
Per Eriksson,Cecilia Lindskog, Ebbe Engholm, Ola Blixt, Jonas Waldenström, Vincent Munster, Åke Lundkvist, Björn Olsen, Elsa Jourdain & Patrik Ellström
Scientific Reports volume 8, Article number: 12215 (2018) | Download Citation


Wild birds of Anseriformes and Charadriiformes are natural reservoirs of influenza A viruses (IAVs). Occasionally, IAVs transmit and adapt to mammalian hosts, and are maintained as epidemic strains in their new hosts. Viral adaptions to mammalian hosts include altered receptor preference of host epithelial sialylated oligosaccharides from terminal α2,3-linked sialic acid (SA) towards α2,6-linked SA.
However, α2,3-linked SA has been found in human respiratory tract epithelium, and human infections by avian IAVs (AIVs) have been reported.

To further explore the attachment properties of AIVs, four AIVs of different subtypes were investigated on human and pig tissues using virus histochemistry. Additionally, glycan array analysis was performed for further characterization of IAVs’ receptor structure tropism.

Generally, AIV attachment was more abundant to human tissues than to pig tissues. The attachment pattern was very strong to human conjunctiva and upper respiratory tract, but variable to the lower respiratory tract. AIVs mainly attached to α2,3-linked SA, but also to combinations of α2,3- and α2,6-linked SA.

The low attachment of these AIV isolates to pig tissues, but high attachment to human tissues, addresses the question whether AIVs in general require passage through pigs to obtain adaptions towards mammalian receptor structures.
Virus-host cell attachment (as determined by virus histochemistry) is a first important step to investigate the propensity of AIV infecting mammalian hosts. However, successful infection and replication is dependent on several additional cumulative factors apart from attachment alone. As exemplified by Kumari et al. the sole existence of α2,3 or α2,6-linked SA on the cell surface is not a warranty for a successful complete IAV replication cycle12. The existence of barriers preventing interspecies transmission of IAVs is well known3,8,9

However, in line with other studies, the reported results suggest that rather than the species barrier being determined by the receptor SA conformation alone, it comprises a combination of additional factors complementary to the receptor structure2,6,17,28,29. Such factors are e.g. the virus’ capacity of evading the host immune response and the ability to replicate efficiently in the infected host cell. Differences in e.g. host immune response and host cell biophysical properties might still require passage through pigs for an AIV to adapt to other mammalian hosts. Indeed, already Scholtissek et al. suggested that IAV host specificity is determined by several factors, and not a single factor6.

Still, as mentioned earlier, there are many reports of infection and replication of AIV in human and pig cells, both in vivo and in vitro21,30,31,32. More extensive histochemistry studies of IAV on human vs. pig sections would be needed in order to fully validate the rationale of the pig as a “mixing vessel” for IAV of avian and mammalian (human) type. 
Such studies should ideally be complemented by infection studies in cell culture, using multiple cell lines and ideally primary cells representing the tissue of interest, to investigate the virus’ ability to replicate30,31,32,33.
Finally, this study shows that AIV of various subtypes from diverse avian species have the capacity to both attach to α2,6-linked SA structures and have a broad capacity of attaching to human tissues.
The zoonotic potential of AIVs can thus not be neglected.
        (Continue . . . . )

While none of this negates that possibility that pigs could help serve up the next pandemic virus - even one of avian origin - it does suggest their participation is optional.

To paraphrase a much used Internet meme . . .  `Viruses, uh, find a way'.


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