#17,859
Despite their increasing spillover into mammalian species, avian influenza viruses like H5N1 and H5N6 still bind preferentially to the alpha 2,3 receptor cells found in the gastrointestinal tract of birds. Humanized’ flu viruses - like seasonal H3N2 and H1N1 - have a strong affinity for the alpha 2,6 receptor cells most commonly found in the human respiratory system.
While other mammalian adaptations are certainly required, the ability of avian flu viruses to bind to human α2-6 receptor cells is considered the single biggest obstacle the virus must overcome in order to successfully spread in humans.
While these exact combinations had not been reported in the wild, a few individual mutations (186G and 193N) had been reported sporadically in H7 isolates.
The following year, in JVI: K193T Mutation Enhances Human-type Receptor Binding In Ferret Transmissible H5N1, we once again saw attention drawn to changes at position 193 in the HA, this time in H5N1. The authors reported:
. . . adding the K193T mutation to the H5 HA of a respiratory droplet transmissible virus dramatically improves both binding to human trachea epithelial cells and specificity for extended α2-6 sialylated N-linked glycans recognized by human influenza viruses.
Today we've a new study, this time out of South Korea, which reports the discovery of a `distinct mutation' (a change from Asparagine (N) to Aspartic acid (D)) at position 193 of the HA in a number of H5N1 isolates collected from wild birds in 2021-2022. The authors noted:
Variations at position 193 of the HA protein exhibit profound implications for influenza viruses, notably, mutations at this position were reported to have an effect on virus adaptability across influenza subtypes, including H5, H3, H7, H9, and H10 [22-27]. The presence of mutations in the HA-193 confers a shift in the receptor binding preference of the virus α2,3 to α2,6 sialic acid or vice versa.
This is a lengthy, and highly technical, paper that many (including myself) will find challenging to get through. Luckily, the gist is fairly simple. The authors performed detailed in vitro and in vivo analyses to determine the impact of this mutation and discovered:
The results revealed that the N193D substitution in the HA RBD altered the binding preference of the virus from avian-like to human-like receptors. More importantly, N193D has a profound effect on growth kinetics and virulence in chicken, mouse, and ferret models, as well as in human respiratory organoids. Our findings highlight the importance of continuous and detailed monitoring as mutations in avian influenzas viruses found in nature pose a great threat to human public health.
The link, and a few excerpts follow. I'll have a postscript after the break.
HA N193D substitution in the HPAI H5N1 virus alters receptor binding affinity and enhances virulence in mammalian hosts
Seung-Gyu Jang, Young-Il Kim, Mark Anthony B Casel, Jeong Ho Choi, Ju Ryeon Gil, Rare Rollon, show all
Article: 2302854 | Accepted author version posted online: 08 Jan 2024
https://doi.org/10.1080/22221751.2024.2302854
Abstract
During the 2021/2022 winter season, we isolated highly pathogenic avian influenza (HPAI) H5N1 viruses harboring an amino acid substitution from Asparagine(N) to Aspartic acid (D) at residue 193 of the hemagglutinin (HA) receptor binding domain (RBD) from migratory birds in South Korea. Herein, we investigated the characteristics of the N193D HA-RBD substitution in the A/CommonTeal/Korea/W811/2021[CT/W811] virus by using recombinant viruses engineered via reverse genetics (RG).
A receptor affinity assay revealed that the N193D HA-RBD substitution in CT/W811 increases α2,6 sialic acid receptor binding affinity. The rCT/W811-HA193N virus caused rapid lethality with high virus titers in chickens compared with the rCT/W811-HA193D virus, while the rCT/W811-HA193D virus exhibited enhanced virulence in mammalian hosts with multiple tissue tropism.
Surprisingly, a ferret-to-ferret transmission assay revealed that rCT/W811-HA193D virus replicates well in the respiratory tract, at a rate about 10 times higher than that of rCT/W811-HA193N, and all rCT/W811-HA193D direct contact ferrets were seroconverted at 10 days post-contact.
Further, competition transmission assay of the two viruses revealed that rCT/W811-HA193D has enhanced growth kinetics compared with the rCT/W811-HA193N, eventually becoming the dominant strain in nasal turbinates. Further, rCT/W811-HA193D exhibits high infectivity in primary human bronchial epithelial (HBE) cells, suggesting the potential for human infection.
Taken together, the HA-193D containing HPAI H5N1 virus from migratory birds showed enhanced virulence in mammalian hosts, but not in avian hosts, with multi-organ replication and ferret-to-ferret transmission. Thus, this suggests that HA-193D change increases the probability of HPAI H5N1 infection and transmission in humans.
Admittedly these mutations are a concern, but it doesn't mean the HPAI H5N1 virus is ready for prime time. There are plenty of other obstacles that these avian viruses must overcome, including:
- 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 human. Which is why we take note of a specific amino acid substitution - PB2 E627K - which can enable avian influenza viruses to replicate at lower temperatures (roughly 33C).
- Other mutations, like the D701N and T271A substitutions in the PB2 - have previously been linked to adaptation and increased virulence in mammals
- There are still other factors, some that we know about (like getting around the interferon-induced host restriction factor MxA), and others that researchers have yet to discover.
And with multiple clades and subclades, numerous subtypes, and hundreds of genotypes circulating, evolving, and reassorting in millions of avian and mammalian hosts, the opportunities for the `right combination' of mutations to emerge only increases with time.
