Avian Flu Diary: PloS Pathogens: Anti-influenza A Virus Restriction Factors that Shape the Human species Barrier and Virus Evolution

Flu Virus binding to Receptor Cells – Credit CDC

#17,534

From time to time we talk about a `species barrier' that protects humans (and other mammals) from infection with avian influenza viruses. After all, were it easy for avian flu viruses to jump species, we'd be hip-deep in new pandemic viruses all the time.

While we don't know all of the barriers to adaptation, two big ones are frequently mentioned.

First, Avian influenza viruses 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 avian viruses have occasionally jumped directly to humans but are rarely passed on to others.

One of the things we are on the lookout for are mutations that may change the binding affinity of avian viruses (see JVI: K193T Mutation Enhances Human-type Receptor Binding In Ferret Transmissible H5N1).

Second, 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).

There are other restrictive factors, some that we know about (like getting around the interferon-induced host restriction factor MxA), and others that researchers have yet to discover.

While the barriers that restrict human adaptation are steep, complex, and only partially understood, they are obviously not insurmountable. All of the `humanized' flu viruses through the ages are believed to have originated in birds, before adapting to mammals.

In 1968, when the world was dominated by the H2N2 flu virus - an avian H3 emerged (H3N2) in Hong Kong - and sparked a pandemic that quickly supplanted H2N2 and killed more than 1 million people.

This virus was a reassortment consisting of 2 genes from a low path avian influenza H3 virus, and 6 genes from H2N2. And while it was not initially as deadly as the 1957 or 1918 pandemics - it is still with us 55 years later - and has caused millions of additional deaths over the past half century.

The H2N2 virus that sparked the 1957 pandemic was also of avian origin. According to the CDC : This H2N2 virus was comprised of three different genes from an H2N2 virus that originated from an avian influenza A virus, including the H2 hemagglutinin and the N2 neuraminidase genes.

The $64 question is whether avian H5 (or H7) viruses have the `right stuff' to overcome these barriers.

As we've discussed often over the past few years (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?), the progression of human influenza pandemics over the past 130 years has been H2, H3, H1, H2, H3, H1, H1 . . . .

Novel H1, H2, and H3 flu viruses appear to have fewer barriers to overcome in order to jump to humans - and while they may not prove as virulent as H5 & H7 avian subtypes - that puts them at or near the top of our pandemic threats list.

But with few exceptions (i.e. the 2009 H1N1 pandemic virus), current swine influenza viruses don't appear to spread efficiently in humans. That said, the CDC's IRAT (Influenza Risk Assessment Tool) lists 3 North American swine viruses as having at least some pandemic potential (2 added in 2019).

H1N2 variant [A/California/62/2018] Jul 2019 5.8 5.7 Moderate
H3N2 variant [A/Ohio/13/2017] Jul 2019 6.6 5.8 Moderate
H3N2 variant [A/Indiana/08/2011] Dec 2012 6.0 4.5 Moderate

The CDC currently ranks a Chinese Swine-variant EA H1N1 `G4' as having the highest pandemic potential of any flu virus on their list. But, as with avian flu, they all have barriers they must overcome.

For those wanting a far more in-depth look at the factors that shape the human species barrier, we have an educational Pearls review, published yesterday in PLos Pathogens. I've only posted some excerpts, so you'll want to follow the link to read it in its entirety.

I'll have a brief postscript when you return.

Anti-influenza A virus restriction factors that shape the human species barrier and virus evolution
Philipp Peter Petric, Martin Schwemmle, Laura Graf

Published: July 6, 2023 https://doi.org/10.1371/journal.ppat.1011450

Introduction

Zoonotic infections with influenza A viruses (IAVs) of avian origin can cause severe disease with high fatality in humans, as in the case of the avian IAV subtypes H5N1 and H7N9. Fortunately, such spillover events from the avian reservoir to humans are rare and mostly limited to single individuals due to a robust species barrier. The molecular basis for this species barrier is the intrinsically poor adaptation of avian IAVs to humans [1]. Avian IAVs are unable to exploit human host factors required for virus replication and to escape anti-IAV restriction factors that serve as gatekeepers for zoonotic IAVs in human cells. As a result, efficient virus replication is hampered and virus spread within the human population is not readily possible.

IAVs, however, constantly evolve. Occasionally, they can acquire the capacity to overcome the human species barrier. This is a very rare event. Yet, all past and current seasonal IAVs circulating in the human population can be traced back to animal reservoirs. IAVs possess an error-prone polymerase that facilitates the acquisition of mutations in the viral genome. Most of these mutations are detrimental for the virus, but some may favor interactions with pro-viral host factors or bypass specific antiviral factors and may be selected because they grant a fitness advantage in the new host [2].

Numerous adaptation steps are required to overcome the species barrier and to achieve sustained circulation in the human population. For zoonotic IAVs of avian origin, the step-wise acquisition of favorable mutations is a major challenge. However, preadaptation in intermediate hosts, such as pigs may facilitate the adaptive process. Another possibility for avian IAVs to overcome the human species barrier is the exchange of viral genome segments with viral strains already adapted to humans by reassortment that may occur in coinfected cells. Examples include the pandemic viruses that caused the Asian influenza of 1957 or the Hong-Kong influenza of 1968. Pigs may play a special role in reassortment because they are equally susceptible to infections with avian and human IAVs and thus provide an ideal environment for the emergence of new strains with pandemic potential. Indeed, multiple reassortments between human, porcine, and avian IAVs over several years led to the 2009 IAV pandemic [2,3].

Many different host factors that are essential for efficient viral replication of IAV in human cells have been described to also contribute to the human species barrier preventing zoonotic IAV infections (for a review see [4]). Here, we review current insights into human, anti-IAV restriction factors that preferentially inhibit zoonotic IAVs and discuss how preadaptation in intermediate hosts may enable IAVs to escape them. In addition, we address how genetic defects in the antiviral response can compromise the human species barrier.

(SNIP)

Conclusions

Anti-IAV restriction factors such as the MxA protein are major components of the human species barrier against transmission of zoonotic IAVs. Most likely, numerous additional host restriction factors are involved and need to be discovered. Such antiviral barriers can be overcome through the acquisition of escape mutations in the viral genome, host genetic defects that compromise innate antiviral defenses, and reassortment events. Preadaptation, including reassortment, in intermediate hosts can also increase the viral fitness of nonhuman IAVs, thereby increasing their zoonotic and pandemic potential. It will be important to monitor the capacity of IAVs originating from diverse animal reservoirs to escape human restriction factors. It will be equally important to identify and protect highly susceptible individuals carrying inactive variants of these essential antiviral host factors.

(Continue . . . .)

Despite our growing concerns over H5N1 (see yesterdays updated CDC assessment), we probably won't know if H5 avian influenza is even capable of sparking a pandemic until we actually see it happen. While I wouldn't bet good money against it, it is probably fair to call it a long-shot.

But H5Nx is only one of scores of avian and swine influenza A viruses in the wild with pandemic potential.

All are continually evolving (via antigenic drift and antigenic shift), many are spilling over into new mammalian species where they may pick up host adaptations - and while individually they may all be long-shots to spark a pandemic - when you have that many rolling the genetic dice, it is pretty much inevitable that one of them will eventually succeed.