Flu Virus binding to Receptor Cells – Credit CDC
#18,477
Over the past 2 decades we've discussed a number of potential `species barriers' that might prevent avian H5 or H7 viruses from ever sparking a pandemic. As far as we can go back in time (about 130 years), all of the known human influenza pandemics have been from an H1, H2, or H3 virus.
What subtypes of influenza that may have circulated in humans before that is unknown.
There are at least three major barriers to avian flu becoming a `humanized' virus.
- First, avian flu viruses bind preferentially to 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.
- Second, birds run `hotter' than mammals, meaning an avian flu virus must adapt to replicate at the lower temperatures found in the human respiratory tract.
- Third, the virus must get around the interferon-induced host restriction factor MxA, which is a protein that provides protection against a broad range of viruses, including some avian influenza viruses.
We've even seen reports of some avian-like viruses that are able to skirt around the MxA antiviral barrier (see Recent Papers On The Zoonotic Potential of Bat-borne H9N2).
But so far, HPAI H5 hasn't managed to pull off the hat-trick; All three at once.
And to be fair, even if that did happen, there may be some other inhibiting factor that could prevent efficient spread in humans. We won't really know if an H5Nx pandemic is possible until it happens.
All of which brings us to an EID Journal research letter which finds - while the current H5N1 clade 2.3.4.4b continues to be suppressed by MxA - there are at least a couple of ways that the H5N1 virus could get around this `species barrier'.
- First, they have already observed that some H5 isolates have shown signs of partial adaptation, via mutations in the PB2 (E627K and M631L), which have weakened the antiviral impact of MxA.
- And second, they warn that an H5 reassortment with a seasonal flu virus (like H1N1 or H3N2) could provide H5N1 with the keys to human adaptation.
The takeaway is that the protection offered by the MxA protein is not absolute, and given the rapid spread and evolution of H5 viruses, MxA escape variants could emerge.
This is admittedly a highly technical review, and I've only covered a few of the highlights, and have only posted some excerpts. Follow the link to read it in its entirety.
Research Letter
Jakob Ankerhold1, Susanne Kessler1, Martin Beer, Martin Schwemmle, and Kevin Ciminski
Abstract
We show that human myxovirus resistance protein 1 (MxA) suppresses replication of highly pathogenic avian influenza A(H5N1) viruses isolated from mammals in vitro and in MxA-transgenic mice. However, H5N1 can evade MxA restriction through replacement of individual viral polymerase complex components from a human-adapted MxA-resistant strain in vitro.
Since 2022, clade 2.3.4.4b highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype have caused an increasing number of outbreaks in mammals worldwide (1). Since spring 2024, outbreaks of H5N1 clade 2.3.4.4b viruses have occurred in dairy cows in the United States, leading to the transmission of the virus to dairy farm workers, likely through close contact with infected cows or milk (2,3). Those events have raised concerns that H5N1 clade 2.3.4.4b viruses may further adapt to humans.
Indeed, some current mammal H5N1 clade 2.3.4.4b isolates already carry adaptive mutations associated with enhanced binding to mammalian entry receptors, increased viral polymerase activity in mammalian cells, or escape from the recently identified BTN3A3 restriction factor (1,2,4). However, for sustained human-to-human transmission, HPAI H5N1 must overcome additional host barriers, including human myxovirus resistance protein 1 (MxA).
MxA is an interferon-induced innate immune protein that suppresses replication of zoonotic influenza A viruses (IAVs) (5,6). Previous studies have demonstrated that human-adapted IAVs, such as the pandemic H1N1 virus A/Hamburg/4/2009 (pH1N1), evade MxA restriction through adaptive amino acids in the viral nucleoprotein (NP) (7). In contrast, MxA escape-mediating amino acids are absent in avian IAVs, such as the human HPAI H5N1 isolate A/Thailand/1(KAN-1)/2004 and the current mamma H5N1 clade 2.3.4.4b isolates (Appendix Figure). We used a risk assessment approach to investigate whether human MxA restricts zoonotic infections with mammalian H5N1 clade 2.3.4.4b isolates.
(SNIP)
Our data show that human MxA restricts current mammalian H5N1 clade 2.3.4.4b isolates. However, because this MxA-mediated restriction was less pronounced in hMxAtg/tg mice, we speculate that adaptations in the viral polymerase, including PB2E627K and PB2M631L within the PB2 627 domain, have enabled the viruses to partially outpace MxA-mediated restriction (10).
Given the ongoing circulation of bovine H5N1 in dairy cattle expressing antivirally active Mx1, increased surveillance could identify the potential emergence of MxA escape variants and provide early warning for possible future human-to-human transmission of these viruses.
Mr. Ankerhold is an MD/PhD student at the Institute of Virology at the Medical Center of the University of Freiburg, Germany. His research interests include zoonotic viruses and molecular host determinants.
